Bicyclic lactams and methods of use thereof

ABSTRACT

The invention provides novel compounds having the general formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , X, Z 1 , L, n, the A ring, the B ring, and the C ring are as described herein, pharmaceutical compositions including the compounds and methods of using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 62/188,153, filed Jul. 2, 2015, and 62/387,295, filed Dec. 23, 2015. The entire contents of the above-referenced applications are hereby incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of RIP1 kinase useful for treating diseases and disorders associated with inflammation, cell death and others.

BACKGROUND OF THE INVENTION

Receptor-interacting protein-1 (“RIP1”) kinase is a serine/threonine protein kinase. RIP1 is a regulator of cell signaling that is involved, among other things, in the mediation of programmed cell death pathways, e.g., necroptosis. The best studied form of necroptotic cell death is initiated by TNFα (tumor necrosis factor), but necroptosis can also be induced by other members of the TNFα death ligand family (Fas and TRAIL/Apo2L), interferons, Toll-like receptors (TLRs) signaling and viral infection via the DNA sensor DAI (DNA-dependent activator of interferon regulatory factor) [1-3]. Binding of TNFα to the TNFR1 (TNF receptor 1) prompts TNFR1 trimerization and formation of an intracellular complex, Complex-I. TRADD (TNF receptor associated death domain protein) binds to the intracellular death domain of TNFR1 and recruits the protein kinase RIP1 (receptor-interacting protein 1) through the death domain present in both proteins [4]. Following initial recruitment into TNFR1-associated signaling complex, RIP1 translocates to a secondary cytoplasmatic complex, Complex-II [5-7]. Complex-II is formed by the death domain containing protein FADD (Fas-associated Protein), RIP1, caspase-8 and cFLIP. If caspase-8 is not fully activated or its activity is blocked, the protein kinase RIP3 gets recruited to the complex, forming a necrosome, which will lead to necroptotic cell death initiation [8-10]. Once the necrosome is formed, RIP1 and RIP3 engage in a series of auto and cross phosphorylation events that are essential for necroptotic cell death. Necroptosis can be completely blocked either by the kinase inactivating mutation in any of the two kinases, or chemically by RIP1 kinase inhibitors (necrostatins), or RIP3 kinase inhibitors [11-13]. Phosphorylation of RIP3 allows the binding and phosphorylation of pseudokinase MLKL (mixed lineage kinase domain-like), a key component of necroptotic cell death [14, 15].

Necroptosis has crucial pathophysiological relevance in myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel diseases, retinal degeneration and a number of other common clinical disorders [16]. Therefore, selective inhibitors of RIP1 kinase activity are therefore desired as a potential treatment of diseases mediated by this pathway and associated with inflammation and/or necroptotic cell death.

Inhibitors of RIP1 kinase have been previously described. The first published inhibitor of RIP1 kinase activity was necrostatin 1 (Nec-1) [17]. This initial discovery was followed by modified versions of Nec-1 with various abilities to block RIP1 kinase activity [11, 18]. Recently, additional RIP1 kinase inhibitors have been described that differ structurally from necrostatin class of compounds [19, 20, 21].

References cited above, each of which is hereby incorporated by reference in its entirety:

-   1) Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S.,     Walczak, H. and Vandenabeele, P. (2014) Regulated necrosis: the     expanding network of non-apoptotic cell death pathways. Nature     reviews. Molecular cell biology. 15, 135-147. -   2) Newton, K. (2015) RIPK1 and RIPK3: critical regulators of     inflammation and cell death. Trends in cell biology. 25, 347-353. -   3) de Almagro, M. C. and Vucic, D. (2015) Necroptosis: Pathway     diversity and characteristics. Semin Cell Dev Biol. 39, 56-62. -   4) Chen, Z. J. (2012) Ubiquitination in signaling to and activation     of IKK. Immunological reviews. 246, 95-106. -   5) O'Donnell, M. A., Legarda-Addison, D., Skountzos, P., Yeh, W. C.     and Ting, A. T. (2007) Ubiquitination of RIP1 regulates an     NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol.     17, 418-424. -   6) Feoktistova, M., Geserick, P., Kellert, B., Dimitrova, D. P.,     Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Hacker, G. and     Leverkus, M. (2011) cIAPs block Ripoptosome formation, a     RIP1/caspase-8 containing intracellular cell death complex     differentially regulated by cFLIP isoforms. Molecular cell. 43,     449-463. -   7) Bertrand, M. J., Milutinovic, S., Dickson, K. M., Ho, W. C.,     Boudreault, A., Durkin, J., Gillard, J. W., Jaquith, J. B.,     Morris, S. J. and Barker, P. A. (2008) cIAP1 and cIAP2 facilitate     cancer cell survival by functioning as E3 ligases that promote RIP1     ubiquitination. Mol Cell. 30, 689-700. -   8) Wang, L., Du, F. and Wang, X. (2008) TNF-alpha induces two     distinct caspase-8 activation pathways. Cell. 133, 693-703. -   9) He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L. and     Wang, X. (2009) Receptor interacting protein kinase-3 determines     cellular necrotic response to TNF-alpha. Cell. 137, 1100-1111. -   10) Cho, Y. S., Challa, S., Moquin, D., Genga, R., Ray, T. D.,     Guildford, M. and Chan, F. K. (2009) Phosphorylation-driven assembly     of the RIP1-RIP3 complex regulates programmed necrosis and     virus-induced inflammation. Cell. 137, 1112-1123. -   11) Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I. L., Korkina,     O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C., Wagner, G.,     Hedrick, S. M., Gerber, S. A., Lugovskoy, A. and Yuan, J. (2008)     Identification of RIP1 kinase as a specific cellular target of     necrostatins. Nat Chem Biol. 4, 313-321. -   12) Newton, K., Dugger, D. L., Wickliffe, K. E., Kapoor, N., de     Almagro, M. C., Vucic, D., Komuves, L., Ferrando, R. E., French, D.     M., Webster, J., Roose-Girma, M., Warming, S. and     Dixit, V. M. (2014) Activity of protein kinase RIPK3 determines     whether cells die by necroptosis or apoptosis. Science. 343,     1357-1360. -   13) Kaiser, W. J., Sridharan, H., Huang, C., Mandal, P., Upton, J.     W., Gough, P. J., Sehon, C. A., Marquis, R. W., Bertin, J. and     Mocarski, E. S. (2013) Toll-like receptor 3-mediated necrosis via     TRIF, RIP3, and MLKL. The Journal of biological chemistry. 288,     31268-31279. -   14) Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J. and     Liu, Z. G. (2012) Mixed lineage kinase domain-like is a key receptor     interacting protein 3 downstream component of TNF-induced necrosis.     Proceedings of the National Academy of Sciences of the United States     of America. 109, 5322-5327. -   15) Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang,     L., Yan, J., Liu, W., Lei, X. and Wang, X. (2012) Mixed Lineage     Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of     RIP3 Kinase. Cell. 148, 213-227. -   16) Linkermann, A. and Green, D. R. (2014) Necroptosis. The New     England journal of medicine. 370, 455-465. -   17) Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P.,     Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A. and     Yuan, J. (2005) Chemical inhibitor of nonapoptotic cell death with     therapeutic potential for ischemic brain injury. Nat Chem Biol. 1,     112-119. -   18) Takahashi, N., Duprez, L., Grootjans, S., Cauwels, A., Nerinckx,     W., DuHadaway, J. B., Goossens, V., Roelandt, R., Van Hauwermeiren,     F., Libert, C., Declercq, W., Callewaert, N., Prendergast, G. C.,     Degterev, A., Yuan, J. and Vandenabeele, P. (2012) Necrostatin-1     analogues: critical issues on the specificity, activity and in vivo     use in experimental disease models. Cell Death Dis. 3, e437. -   19) Harris, P. A., Bandyopadhyay, D., Berger, S. B., Campobasso, N.,     Capriotti, C. A., Cox, J. A., Dare, L., Finger, J. N., Hoffman, S.     J., Kahler, K. M., Lehr, R., Lich, J. D., Nagilla, R., Nolte, R. T.,     Ouellette, M. T., Pao, C. S., Schaeffer, M. C., Smallwood, A.,     Sun, H. H., Swift, B. A., Totoritis, R. D., Ward, P., Marquis, R.     W., Bertin, J. and Gough, P. J. 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SUMMARY OF THE INVENTION

Provided herein are compounds of formula I:

or pharmaceutically acceptable salts thereof, wherein R¹ is selected from the group consisting of H, C₁-C₄ alkyl and C₁-C₄ haloalkyl; the A ring is selected from the group consisting of cyclopropyl, 6 membered aryl, and 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the A ring is optionally substituted with:

-   -   (a) 1 to 3 substituents selected from the group consisting of         halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆         alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl,         benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl);         wherein if a nitrogen atom in the A ring is substituted, the         substituent is not halogen, cyano, or a C₁-C₆ alkoxy, C₁-C₆         haloalkoxy or C₁-C₆ thioalkyl having an oxygen or sulfur atom         directly bonded to the nitrogen atom;     -   (b) 1 substituent selected from the group consisting of C₄-C₆         heterocyclyl, C₅-C₆ heteroaryl, CH₂—(C₄-C₆ heterocyclyl),         CH₂CH₂—(C₄-C₆ heterocyclyl), CH₂CH₂CH₂—(C₄-C₆ heterocyclyl),         CH₂—(C₅-C₆ heteroaryl), CH₂CH₂—(C₅-C₆ heteroaryl);         CH₂CH₂CH₂—(C₅-C₆ heteroaryl); and optionally a second         substituent selected from the group consisting of C₁-C₆ alkyl,         C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and C₁-C₆ haloalkoxy; or     -   (c) two adjacent substituents which together form phenyl, C₅-C₆         heteroaryl, C₄-C₆ heterocyclyl or C₄-C₆ cycloalkyl;         the B ring is tetrazolyl or a 5 to 6 membered heteroaryl having         1 to 3 heteroatoms selected from the group consisting of         nitrogen, oxygen and sulfur; wherein the B ring is optionally         substituted with 1 to 2 substituents selected from the group         consisting of halogen, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄         haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and cyano; and wherein         if a nitrogen atom in the B ring is substituted, the substituent         is not halogen, cyano, or a C₁-C₆ alkoxy, C₁-C₆ haloalkoxy or         C₁-C₆ thioalkyl having an oxygen or sulfur atom directly bonded         to the nitrogen atom;         the C ring is selected from the group consisting of phenyl, 5 to         6 membered heteroaryl, 4 to 7 membered cycloalkyl, and 4 to 7         membered heterocyclyl; wherein the C ring is optionally         substituted with:     -   (a) 1 to 4 substituents selected from the group consisting of         halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆         alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl,         benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl);         wherein if a nitrogen atom in the C ring is substituted, the         substituent is not halogen, cyano, or a C₁-C₆ alkoxy, C₁-C₆         haloalkoxy or C₁-C₆ thioalkyl having an oxygen or sulfur atom         directly bonded to the nitrogen atom;     -   (b) 1 to 2 substituents selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         CH₂—(C₄-C₆ heterocyclyl), CH₂CH₂—(C₄-C₆ heterocyclyl), and         unsubstituted C₅-C₆ heteroaryl; or     -   (c) two adjacent substituents which together form phenyl, C₅-C₆         heteroaryl, C₄-C₆ heterocyclyl or C₄-C₆ cycloalkyl;         L is selected from the group consisting of a bond, O, S, NH,         NCH₃, (CH₂)_(m), CH(CH₃), C(CH₃)₂, CF₂, CH₂O, CH₂S, CH(OH),         CH₂NH, and CH₂N(CH₃), or L is absent such that the B ring and         the C ring are fused;         X is selected from the group consisting of O, S, SO, SO₂, CH₂,         C(CH₃)₂, CF₂ and CHCF₃;         Z¹ is selected from the group consisting of:     -   (i) C and N when the A ring is a 5 or 6 membered heteroaryl,     -   (ii) C when the A ring is a 6 membered aryl, and     -   (iii) CH when the A ring is cyclopropyl;         m is 1 or 4; and         n is 1 or 2;         provided that if the A ring is 6 membered aryl or 6 membered         heteroaryl, L is absent such that the B ring and the C ring are         fused;         further provided that if the A ring is a 5 to 6 membered         heteroaryl having 3 heteroatoms, two of said heteroatoms must be         nitrogen;         further provided that if the A ring is unsubstituted 6 membered         aryl and L is absent, the fused B and C rings are not         unsubstituted indolyl or indolyl substituted by one or two         halogen atoms; and         further provided that if the B ring is tetrazolyl, L is selected         from the group consisting of CH₂, CH(CH₃), C(CH₃)₂, CF₂; and the         C ring is phenyl.

In the following description, all references to formula I also include subembodiments of formula I (i.e., formulae 1a, 1b, etc.).

Also provided herein are pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for intravenous or oral delivery.

Also provided herein are oral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery.

Also provided herein are parenteral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for parenenteral delivery.

In some embodiments, provided herein are uses of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of diseases and disorders. In some embodiments, the diseases and disorders to be treated are selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cisplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD).

In some embodiments, the disease or disorder to be treated is selected from the group consisting of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, liver damage/diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury(AKI)), Celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atropy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency ((also known as RBCKI) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as tuberculosis and influenza), and Lysosomal storage diseases (particularly, Gaucher Disease, and including GM2, Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, Cholesteryl Ester storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease, Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Infantile Free Sialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Metachromatic Leukodystrophy, Mucopolysaccharidoses disorders, Multiple sulfatase deficiency, Niemann-Pick Disease, Neuronal Ceroid Lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease, Schindler disease, Sialic Acid Storage Disease, Tay-Sachs and Wolman disease).

In some embodiments, the diseases and disorders to be treated are selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cisplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa and retinal degeneration.

In some embodiments, provided herein are methods for the treatment or prevention of a disease or disorder with a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with inflammation and/or necroptosis. In some embodiments said disease or disorder is selected from the specific diseases and disorders recited herein.

In some embodiments, provided herein are methods of inhibiting RIP1 kinase activity by contacting a cell with a compound of formula I or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As provided herein, all chemical formulae and generic chemical structures should be interpreted to provide proper valence and chemically stable bonds between atoms as understood by one of ordinary skill in the art. Where appropriate, substituents may be bonded to more than one adjacent atom (e.g., alkyl includes methylene where two bonds are present).

In the chemical formulae provided herein, “halogen” or “halo” refers to flurorine, chlorine, and bromine (i.e., F, Cl, Br).

Alkyl, unless otherwise specifically defined, refers to an optionally substituted, straight-chain or branched C₁-C₁₂ alkyl group. In some embodiments, alkyl refers to a C₁-C₆ alkyl group. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-oxtyl. Substituted alkyl groups provided herein are substituted by one or more substituents selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C₃-C₆ cycloalkyl, phenyl, OH, CO₂H, CO₂(C₁-C₄ alkyl), NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl)₂, NH(C═O)C₁-C₄ alkyl, (C═O)NH(C₁-C₄ alkyl), (C═O)N(C₁-C₄ alkyl)₂, S(C₁-C₄ alkyl), SO(C₁-C₄ alkyl), SO₂(C₁-C₄ alkyl), SO₂NH(C₁-C₄ alkyl), SO₂N(C₁-C₄ alkyl)₂, and NHSO₂(C₁-C₄ alkyl). In some embodiments, the substituted alkyl group has 1 or 2 substituents. In some embodiments, the alkyl group is unsubstituted.

Cycloalkyl, unless otherwise specifically defined, refers to an optionally substituted C₃-C₁₂ cycloalkyl group and includes fused, spirocyclic, and bridged bicyclic groups, wherein the substituents are selected from the group consisting of halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C₃-C₆ cycloalkyl, phenyl, OH, CO₂H, CO₂(C₁-C₄ alkyl), NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄ alkyl)₂, NH(C═O)C₁-C₄ alkyl, (C═O)NH(C₁-C₄ alkyl), (C═O)N(C₁-C₄ alkyl)₂, S(C₁-C₄ alkyl), SO(C₁-C₄ alkyl), SO₂(C₁-C₄ alkyl), SO₂NH(C₁-C₄ alkyl), SO₂N(C₁-C₄ alkyl)₂, and NHSO₂(C₁-C₄ alkyl). In some embodiments, cycloalkyl refers to a C₃-C₆ cycloalkyl group. In some embodiments, the C₃-C₆ cycloalkyl group is optionally substituted with 1 to three halogen atoms. In some embodiments, the C₃-C₆ cycloalkyl group is optionally substituted with 1 to three fluorine atoms. Exemplary C₃-C₆ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Exemplary C₃-C₁₂ cycloalkyl groups further include bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicycle[4.1.0]heptyl, spiro[4.2]heptyl, cyclooctyl, spiro[4.3]octyl, spiro[5.2]octyl, bicyclo[2.2.1]heptanyl, bicycle[2.2.2]octanyl, adamantanyl, decalinyl, and spiro[5.4]decanyl. Where appropriate, cycloalkyl groups may be fused to other groups such that more than one chemical bond exists between the cycloalkyl group and another ring system (e.g., the C ring of formula I). In some embodiments, the cycloalkyl group is unsubstituted.

Haloalkyl, unless otherwise specifically defined, refers to a straight-chain or branched C₁-C₁₂ alkyl group, wherein one or more hydrogen atoms are replaced by a halogen. In some embodiments, haloalkyl refers to a C₁-C₆ haloalkyl group. In some embodiments, 1 to 3 hydrogen atoms of the haloalkyl group are replaced by a halogen. In some embodiments, every hydrogen atom of the haloalkyl group is replaced by a halogen (e.g, trifluoromethyl). In some embodiments, the haloalkyl is as defined herein wherein the halogen in each instance is fluorine. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluromethyl, trifluoroethyl, and pentafluoroethyl.

Alkoxy, unless otherwise specifically defined, refers to a straight-chain or branched C₁-C₁₂ alkyl group, wherein one or more oxygen atoms are present, in each instance between two carbon atoms. In some embodiments, alkoxy refers to a C₁-C₆ alkoxy group. In some embodiments, C₁-C₆ alkoxy groups provided herein have one oxygen atom. Exemplary alkoxy groups include methoxy, ethoxy, CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂CH₂CH₂OCH₃, CH₂OCH(CH₃)₂, CH₂OC(CH₃)₃, CH(CH₃)OCH₃, CH₂CH(CH₃)OCH₃, CH(CH₃)OCH₂CH₃, CH₂OCH₂OCH₃, CH₂CH₂OCH₂CH₂OCH₃, and CH₂OCH₂OCH₂OCH₃.

Cycloalkoxy, unless otherwise specifically defined, refers to a C₄-C₁₀ or a C₄-C₆ alkoxy group as defined above wherein the group is cyclic and contains one oxygen atom. Exemplary cycloalkoxy groups include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

Haloalkoxy, unless otherwise specifically defined, refers to a C₁-C₆ haloalkyl group as defined above, wherein one or two oxygen atoms are present, in each instance between two carbon atoms. In some embodiments, C₁-C₆ haloalkoxy groups provided herein have one oxygen atom. Exemplary haloalkoxy groups include OCF₃, OCHF₂ and CH₂OCF₃.

Thioalkyl, unless otherwise specifically defined, refers to a C₁-C₁₂ or a C₁-C₆ alkoxy group as defined above wherein the oxygen atom is replaced by a sulfur atom. In some embodiments, thioalkyl groups may include sulfur atoms substituted by one or two oxygen atoms (i.e., alkylsulfones and alkylsulfoxides). Exemplary thioalkyl groups are those exemplified in the definition of alkoxy above, wherein each oxygen atom is replaced by a sulfur atom in each instance.

Thiocycloalkyl, unless otherwise specifically defined, refers to a C₄-C₁₀ or a C₄-C₆ thioalkyl group as defined above wherein the group is cyclic and contains one sulfur atom. In some embodiments, the sulfur atom of the thiocycloalkyl group is substituted by one or two oxygen atoms (i.e., a cyclic sulfone or sulfoxide). Exemplary thiocycloalkyl groups include thietanyl, thiolanyl, thianyl, 1,1-dioxothiolanyl, and 1,1-dioxothianyl.

Heterocyclyl, unless otherwise specifically defined, refers to a single saturated or partially unsaturated 4 to 8 membered ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems have from 7 to 12 atoms and are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, 7 or 8 membered rings) from about 1 to 7 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.

The ring may be C-branched (i.e., substituted by C₁-C₄ alkyl). The ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system. It is also to be understood that the point of attachment for a heterocycle or heterocycle multiple condensed ring system can be at any suitable atom of the heterocyclyl group including a carbon atom and a nitrogen atom. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrhydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

In some embodiments, the heterocyclyl is a C₄-C₁₀ heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl group is neither bicyclic nor spirocyclic. In some embodiments, the heterocyclyl is a C₅-C₆ heterocylcyl having 1 to 3 heteroatoms, wherein at least 2 are nitrogen if 3 heteroatoms are present.

Aryl, unless otherwise specifically defined, refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic and wherein the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Exemplary aryl groups include phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

Heteroaryl, unless otherwise specifically defined, refers to a 5 to 6 membered aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems having 8 to 16 atoms that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (to form for example a 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has 1 to 15 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system. It is also to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b,4,4a, 5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.

As used herein, the term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

As used herein, the term “C-linked” means that the group that the term describes is attached the remainder of the molecule through a ring carbon atom.

As used herein, the term “N-linked” means that the group that the term describes is attached to the remainder of the molecule through a ring nitrogen atom.

“Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 97% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 98% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

As used herein, the term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water.

As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenyl sulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenedi amine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds which are in a prodrug form. As used herein the term “prodrug” refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester. As another example, compounds of this invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C₁₋₆)alkanoyloxymethyl, 1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl, (C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₆)alkoxycarbonylaminomethyl, succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites of compounds of the invention. As used herein, a “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

Metabolite products typically are identified by preparing a radiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.

The term “composition,” as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The terms “treat” and “treatment” refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.

The phrase “therapeutically effective amount” or “effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).

The term “bioavailability” refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form.

Inhibitors of RIP1 Kinase

The present invention provides novel compounds having the general formula I:

wherein R¹, X, Z¹, L, n, the A ring, the B ring, and the C ring are as described herein.

In some embodiments of formula (I), the A ring is selected from the group consisting of cyclopropyl, 6 membered aryl, and 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the A ring is optionally substituted with:

-   -   (a) 1 to 3 substituents selected from the group consisting of         halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆         alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl,         benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl);         wherein if a nitrogen atom in the A ring is substituted, the         substituent is not halogen, cyano, or a C₁-C₆ alkoxy, C₁-C₆         haloalkoxy or C₁-C₆ thioalkyl having an oxygen or sulfur atom         directly bonded to the nitrogen atom;     -   (b) 1 substituent selected from the group consisting of C₄-C₆         heterocyclyl, C₅-C₆ heteroaryl, CH₂—(C₄-C₆ heterocyclyl),         CH₂CH₂—(C₄-C₆ heterocyclyl), CH₂—(C₅-C₆ heteroaryl),         CH₂CH₂—(C₅-C₆ heteroaryl); and optionally a second substituent         selected from the group consisting of C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ alkoxy, and C₁-C₆ haloalkoxy; or     -   (c) two adjacent substituents which together form phenyl, C₅-C₆         heteroaryl, C₄-C₆ heterocyclyl or C₄-C₆ cycloalkyl; and         the C ring is selected from the group consisting of phenyl, 5 to         6 membered heteroaryl, 5 to 7 membered cycloalkyl, and 5 to 7         membered heterocyclyl; wherein the C ring is optionally         substituted with:     -   (d) 1 to 4 substituents selected from the group consisting of         halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆         alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl,         benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl);         wherein if a nitrogen atom in the C ring is substituted, the         substituent is not halogen, cyano, or a C₁-C₆ alkoxy, C₁-C₆         haloalkoxy or C₁-C₆ thioalkyl having an oxygen or sulfur atom         directly bonded to the nitrogen atom;     -   (e) 1 to 2 substituents selected from the group consisting of         C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,         CH₂—(C₄-C₆ heterocyclyl), CH₂CH₂—(C₄-C₆ heterocyclyl), and         unsubstituted C₅-C₆ heteroaryl; or     -   (f) two adjacent substituents which together form phenyl, C₅-C₆         heteroaryl, C₄-C₆ heterocyclyl or C₄-C₆ cycloalkyl.

In some embodiments, R¹ is selected from the group consisting of H, methyl, ethyl and isopropyl. In some embodiments, R¹ is H. In other embodiments, R¹ is methyl.

In some embodiments, X is CH₂. In some embodiments, X is CF₂. In some embodiments, X is O and Z¹ is C. In some embodiments, X is S and Z¹ is C.

In some embodiments, X is O, Z¹ is CH and the A ring is cyclopropyl.

In some embodiments, L is (CH₂)_(m) and m is 1 or 2. In some embodiments, L is (CH₂)_(m) and m is 1. In other embodiments, L is absent such that the B ring and the C ring are fused.

In some embodiments, n is 1.

In some embodiments, the A ring is cyclopropyl. In some embodiments, the A ring is unsubstituted cyclopropyl. In some embodiments, the A ring is cyclopropyl substituted by 1 to 2 C₁-C₄ alkyl groups. In some embodiments, the A ring is cyclopropyl substituted by one substituent selected from the group consisting of C₁-C₄ alkyl, phenyl or benzyl. In some embodiments, the A ring is cyclopropyl substituted by one or two halogens. In some embodiments, the A ring is as defined in this paragraph and n is 1. In some embodiments, the A ring is as defined in this paragraph, and X is selected from the group consisting of CH₂, C(CH₃)₂, CF₂ and CHCF₃.

In some embodiments, the A ring is a 5 membered heteroaryl having 1 to 2 nitrogen atoms and 0 to 1 oxygen or sulfur atoms as the only heteroatoms. In some embodiments, the A ring is a 5 membered heteroaryl having 1 to 2 nitrogen atoms and 0 to 1 oxygen or sulfur atoms as the only heteroatoms, wherein the 5 membered heteroaryl is unsubstituted or is substituted by C₁-C₄ alkyl. In some embodiments, the A ring is a 5 membered heteroaryl having 2 nitrogen atoms as the only heteroatoms, wherein the 5 membered heteroaryl is unsubstituted or is substituted by C₁-C₄ alkyl. In some embodiments wherein the A ring is as defined in this paragraph, X is CH₂ or O.

In some embodiments, the A ring is an unsubstituted 6 membered aryl. In some embodiments, the A ring is a 6 membered aryl substituted by one or two substituents selected from the group consisting of halogen and C₁-C₄ alkyl. In some embodiments, the A ring is a 6 membered aryl substituted by one or two substituents selected from the group consisting of halogen and methyl. In some embodiments, the A ring is a 6 membered aryl substituted by one or two substituents selected from the group consisting of fluoro and methyl.

In some embodiments, the B ring is a 5 or 6 membered heteroaryl having from 1 to 3 nitrogen atoms in the ring. In other embodiments, the B ring is a 5 or 6 membered heteroaryl having from 1 to 2 nitrogen atoms and from 0 to 1 oxygen or sulfur atoms in the ring. In some embodiments, the B ring is selected from the group consisting of furanyl, pyrroyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and triazolyl. In some embodiments, the B ring is pyrazolyl. In some embodiments, the B ring is imidazolyl. In some embodiments, the B ring is oxazolyl. In some embodiments, the B ring is thiazolyl. In some embodiments, the B ring is triazolyl. In some embodiments, the B ring is oxadiazolyl. In some embodiments, the B ring is pyridinyl or pyrimidinyl. In some embodiments of this paragraph, the B ring is unsubstituted.

In some embodiments wherein L is absent such that the B and C rings are fused, the C ring is a 5 to 7 membered heterocyclyl containing 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In one embodiment wherein L is absent such that the B and C rings are fused, the C ring is a 5 to 7 membered heterocyclyl containing 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. In other embodiments wherein L is absent such that the B and C rings are fused, the C ring is a 5 to 7 membered cycloalkyl. In other embodiments wherein L is absent such that the B and C rings are fused, the C ring is phenyl. In some embodiments of this paragraph, the C ring is unsubstituted.

In some embodiments wherein L is present, the C ring is phenyl substituted by 1 or 2 substituents selected from the group consisting of halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy. In other embodiments wherein L is present, the C ring is unsubstituted phenyl.

In some embodiments, provided herein is a compound of formula I(a):

or a pharmaceutically acceptable salt thereof, wherein R¹, X, Z¹, L, n, the A ring, the B ring, and the C ring are as described herein, wherein Z², Z³, and Z⁴ are each independently selected from the group consisting of CR^(Z) and NR⁸; each R^(Z) is independently selected from the group consisting of H, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CH₂(C₃-C₆ cycloalkyl), C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, CH₂(C₄-C₆ cycloalkoxy), CH₂(C₄-C₆ thiocycloalkyl), phenyl, benzyl, 4 to 6 membered heterocyclyl; and 5 to 6 membered heteroaryl; each R⁸ is either absent if the nitrogen atom to which it is attached has three bonds to other atoms, or R⁸ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CH₂(C₃-C₆ cycloalkyl), C₁-C₆ haloalkyl, CH₂(C₄-C₆ cycloalkoxy), CH₂(C₄-C₆ thiocycloalkyl), phenyl, and benzyl; wherein Z¹ is N only if X is CH₂, CF₂, CH(CH₃), CH(CF₃), C(CH₃)₂, or CH(OH); wherein if Z¹ is N, at least one of Z², Z³ or Z⁴ is CR^(Z); wherein, when Z² and Z³ are each independently selected from CR^(Z) and NR⁸, Z² and Z³ together with their respective R^(Z) and R⁸ substituents may form a 6 membered aryl, 6 membered heteroaryl, 5 to 6 membered cycloalkyl or 5 to 6 membered heterocyclyl group; wherein, when Z³ and Z⁴ are each independently selected from CR^(Z) and NR⁸, Z³ and Z⁴ together with their respective R^(Z) and R⁸ substituents may form a 6 membered aryl, 6 membered heteroaryl, 5 to 6 membered cycloalkyl or 5 to 6 membered heterocyclyl group;

In some embodiments of formula I(a), R¹ is selected from H and CH₃. In some embodiments, R¹ is H. In other embodiments, R¹ is CH₃.

In some embodiments of formula I(a), X is CH₂ or O; Z¹ is C; and Z², Z³, and Z⁴ are each independently selected from the group consisting of CR^(Z), NH, NCH₃. In some embodiments of formula I(b), X is CH₂ or O; Z¹ is C; and Z², Z³, and Z⁴ are each independently selected from the group consisting of CH and NH.

In some embodiments of formula I(a), X is CH₂; Z¹ is N; and Z², Z³, and Z⁴ are each independently selected from the group consisting of CR^(Z), NH, NCH₃, wherein at least one of Z², Z³, and Z⁴ is CR^(Z). In some embodiments of formula I(a), X is CH₂; Z¹ is N; and Z², Z³, and Z⁴ are each independently selected from the group consisting of CH and NH, wherein at least one of Z², Z³, and Z⁴ is CH.

In some embodiments of formula I(a), n is 1.

In some embodiments of formula I(a), the compound is of a formula selected from the group consisting of:

wherein each R⁹ is independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms, C₁-C₆ haloalkyl, (C₁-C₄ alkoxy)-C₁-C₂ alkyl, phenyl, benzyl, C₄-C₆ heterocyclyl, CH₂—(C₃-C₆ cycloalkyl), CH₂—(C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms), and CH₂—(C₄-C₆ heterocyclyl).

In some embodiments, each R⁹ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CH₂CH₂OCH₃, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkyl substituted by 1 to 2 fluorine atoms, CH₂—(C₃-C₄ cycloalkyl), CH₂—(C₃-C₄ cycloalkyl substituted by 1 to 2 fluorine atoms), and CH₂—(C₄ heterocyclyl).

In some embodiments of formula I(a), the compound is of a formula selected from the group consisting of:

In some of the above embodiments of formula I(a), R¹ is H or methyl.

In some embodiments, provided herein is a compound of formula I(b):

or a pharmaceutically acceptable salt thereof, wherein R¹, X, L, n, the A ring, the B ring, and the C ring are as described herein, wherein

Z¹ is CH; and

R² and R³ are each independently selected from the group consisting of H, halo, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CO₂(C₁-C₆ alkyl), phenyl, benzyl, 5 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, —CH₂(C₃-C₆ cycloalkyl), and —CH₂(C₄-C₆ heterocyclyl); provided that when each of R² and R³ are other than H or halo, one must be C₁-C₄ alkyl.

In some embodiments of formula I(b), R² and R³ are each independently selected from the group consisting of H, fluoro, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CO₂(C₁-C₆ alkyl), phenyl, benzyl, 5 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, —CH₂(C₃-C₆ cycloalkyl), and —CH₂(C₄-C₆ heterocyclyl); provided that when each of R² and R³ are other than H or fluoro, one must be C₁-C₄ alkyl.

In some embodiments of formula I(b), R² and R³ are each independently H or C₁-C₆ alkyl.

In some embodiments of formula I(b), R¹ is H or methyl.

In some embodiments, provided herein is a compound of formula I, I(a) and I(b) wherein

is selected from the group consisting of:

Y is selected from the group consisting of O, S, SO and SO₂; X¹, X² and X³ are each independently N or CH, wherein 1 or 2 of X¹, X² and X³ is N; X⁴ and X⁵ are each independently N or CH; R^(5a) and R^(5b), are each independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenyl, benzyl, —CH₂(C₃-C₆ cycloalkyl); and 5 to 6 membered heteroaryl; wherein R^(5a) and R^(5b) together with the carbon to which they are attached may form a 3 to 5 membered cycloalkyl optionally substituted by one or two fluoro, or a 4 to 5 membered cycloalkoxy; R^(6a) and R^(6b) are each independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH₂(C₃-C₆ cycloalkyl), and 5 to 6 membered heteroaryl; wherein R^(6a) and R^(6b) together with the carbon to which they are attached may form a 3 to 5 membered cycloalkyl optionally substituted by one or two fluoro, or a 4 to 5 membered cycloalkoxy; wherein when R^(5a) and R^(6a) are each H, R^(5b) and R^(6b) may together form a 3 or 4 membered cycloalkyl; and wherein only two of R^(5a), R^(5b), R^(6a) and R^(6b) may be other than H in each instance; R⁷ is selected from the group consisting of H, unsubstituted C₁-C₄ alkyl, C₃-C₆ cycloalkyl, and C₄-C₆ cycloalkoxy; R¹⁰ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, phenyl, and benzyl; and R¹¹ is selected from the group consisting of H, halogen, cyano, C₁-C₄ alkyl, and C₁-C₄ haloalkyl.

In some embodiments, Y is O.

In some embodiments, R^(5a) and R^(5b) are each H.

In some embodiments, R^(5a) and R^(5b) are each H; and R^(6a) and R^(6b) are each independently C₁-C₄ alkyl. In some embodiments, R^(5a) and R^(5b) are each H; R^(6a) is H; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl. In some embodiments, R^(5a) and R^(5b) are each H; R^(6a) is H; and R^(6b) is C₁-C₄ alkyl or C₁-C₄ haloalkyl. In some embodiments, R^(5a) and R^(5b) are each H; R^(6a) is methyl; and R^(6b) is C₁-C₄ alkyl or C₃-C₄ cycloalkyl. In some embodiments, R^(5a) and R^(5b) are each H; R^(6a) is methyl; and R^(6b) is phenyl.

In some embodiments, R^(5a) and R^(6a) are each H, and R^(5b) and R^(6b) together form cyclopropyl or cyclobutyl; and Y is O.

In some embodiments, R⁷ is H or methyl.

In some embodiments, R¹⁰ is selected from the group consisting of H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, phenyl, and benzyl.

In some embodiments, R¹¹ is selected from the group consisting of H, halogen, methyl, and trifluromethyl.

In some embodiments, provided herein is a compound of formula I, I(a) and I(b) wherein

is selected from the group consisting of:

wherein R^(5b), R^(5b), R^(6a), R^(6b), R⁷, R¹⁰ and R¹¹ are as defined above; and Y is O.

In some embodiments, provided herein is a compound of formula I, I(a) and I(b) wherein

is selected from the group consisting of:

wherein R^(6a) and R¹¹ are as defined above. In some embodiments, R^(6a) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl or phenyl. In some embodiments, R¹¹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl or phenyl.

In some embodiments, provided herein is a compound of formula I, I(a) or I(b) wherein

wherein R^(6a) and R^(6b) are as defined above. In some embodiments, R^(6a) and R^(6b) are each independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl or phenyl; provided that if one of R^(6a) and R^(6b) is phenyl, the other is H. In some embodiments, R^(6a) and R^(6b) together form C₃-C₆ cycloalkyl.

In some embodiments, provided herein is a compound of formula I, I(a) or I(b) wherein

wherein R^(6a) is as defined above. In some embodiments, R^(6a) is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl or phenyl. In some embodiments, R^(6a) is phenyl.

In some embodiments, provided herein is a compound of formula I(a) or I(b), wherein

is selected from the group consisting of:

wherein R¹² is selected from the group consisting of halogen and methyl; and t is 0, 1 or 2.

In some embodiments, R¹² is fluoro and t is 1 or 2. In some embodiments, t is 0.

In some embodiments, provided herein is a compound of formula I(a) or I(b), wherein

wherein R¹² and t are as defined above. In some embodiments, each R¹² is selected from fluoro and chloro. In some embodiments, each R¹² is F and t is 1 or 2.

In some embodiments, provided herein is a compound of formula I(a) or I(b), wherein

wherein R¹² and t are as defined above. In some embodiments, each R¹² is selected from fluoro and chloro. In some embodiments, each R¹² is F and t is 1 or 2.

Also provided herein are specific stereoisomers of the compounds of each of the above embodiments of formulae I, I(a) and I(b):

and each of the substituents are as defined above.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein each of the substituents are as defined above.

In some embodiments provided herein is a compound of formula I(a) of the formula:

wherein R¹ is H, methyl or ethyl; R⁹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms, C₁-C₆ haloalkyl, (C₁-C₄ alkoxy)-C₁-C₂ alkyl, phenyl and benzyl; R¹² is F or Cl; and t is 0, 1, 2 or 3. In some embodiments, R¹ is methyl; R⁹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms; R¹² is F; and t is 0, 1 or 2.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein each of the substituents are as defined above.

In some embodiments, provided herein is a compound of formula I(a)(i) of the formula:

wherein R¹ is H, methyl or ethyl; R⁹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms, C₁-C₆ haloalkyl, (C₁-C₄ alkoxy)-C₁-C₂ alkyl, phenyl and benzyl; R¹² is F or Cl; and t is 0, 1, 2 or 3. In some embodiments, R¹ is methyl; R⁹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms; R¹² is F; and t is 0, 1 or 2.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein R¹, the A ring, Z¹, X, and R^(6b) are as defined herein. In some embodiments, R¹ is H, methyl or ethyl. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is as defined herein. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein R¹, the A ring, Z¹, X, and R^(6b) are as defined herein. In some embodiments, R¹ is H, methyl or ethyl. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is as defined herein. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein R¹, the A ring, Z¹, X, and R^(6b) are as defined herein, and Y is NH or O. In some embodiments, R¹ is H, methyl or ethyl. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is as defined herein. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein each R¹³ is halo or C₁-C₄ alkyl, v is 0 to 2; and R¹, X, and R^(6b) are as defined herein. In some embodiments, R¹ is H, methyl or ethyl. In some embodiments, R¹ is H or methyl; X is CH₂ or O; and R^(6b) is as defined herein. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl. In some embodiments, each R¹³ is F or methyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein each R¹³ is halo or C₁-C₄ alkyl, v is 0 to 2; and R¹, X, and R^(6b) are as defined herein. In some embodiments, R¹ is H, methyl or ethyl. In some embodiments, R¹ is H or methyl; X is CH₂ or O; and R^(6b) is as defined herein. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl. In some embodiments, each R¹³ is F or methyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein each R¹³ is halo or C₁-C₄ alkyl, v is 0 to 2; Y is NH or O; and R¹, X, and R^(6b) are as defined herein. In some embodiments, R¹ is H, methyl or ethyl. In some embodiments, R¹ is H or methyl; X is CH₂ or O; and R^(6b) is as defined herein. In some embodiments, R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; X is CH₂ or O; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl. In some embodiments, each R¹³ is F or methyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein R⁹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms, C₁-C₆ haloalkyl, (C₁-C₄ alkoxy)-C₁-C₂ alkyl, phenyl and benzyl; and R^(6b) is as defined herein. In some embodiments, R⁹ is H, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl, benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl). In some embodiments, R⁹ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl, phenyl, fluorophenyl or di-fluorophenyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein R⁹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms, C₁-C₆ haloalkyl, (C₁-C₄ alkoxy)-C₁-C₂ alkyl, phenyl and benzyl; and R^(6b) is as defined herein. In some embodiments, R⁹ is H, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl, benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl). In some embodiments, R⁹ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl, phenyl, fluorophenyl or di-fluorophenyl.

In some embodiments, provided herein is a compound of formula I(a) of the formula:

wherein Y is NH or O; R⁹ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms, C₁-C₆ haloalkyl, (C₁-C₄ alkoxy)-C₁-C₂ alkyl, phenyl and benzyl; and R^(6b) is as defined herein. In some embodiments, R⁹ is H, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl or phenyl optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl, benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl). In some embodiments, R⁹ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl; and R^(6b) is C₁-C₄ alkyl, C₁-C₄ haloalkyl, phenyl, fluorophenyl or di-fluorophenyl.

Also provided herein are embodiments corresponding to each of those described above, wherein each substituent is unsubstituted unless explicity provided in the embodiment.

Particular compounds of formulae I, I(a), I(b) and II (hereafter referred to collectively as “formula I”) include the following, wherein each compound is the result of a condensation between a “left-hand side” amine (LHS Amine) of Table A, and a “right-hand side” carboxylic acid (RHS Acid) of Table A to form an amide of formula I. For simplicity, hydrogens are not shown. All possible combinations of a LHS Amine with a RHS Acid are contemplated and within the scope of the invention.

TABLE A LHS Amine RHS Acid 1

1 2

2 3

3 4

4 5

5 6

6 7

7 8

8 9

9 10

10 11

11 12

12 13

13 14

14 15

15 16

16 17

17 18

18 19

19 20

20 21

21 22

22 23

23 24

24 25

25 26

26 27

27 28

28 29

29 30

30 31

31 32

32 33

33 34

34 35

35 36

36 37

37 38

38 39

39 40

40 41

41 42

42 43

43 44

44 45

45 46

46 47

47 48

48 49

49 50

50 51

51 52

52 53

53 54

54 55

55 56

56 57

57 58

58 59

59 60

60 61

61 62

62 63

63 64

64 65

65 66

66 67

67 68

68 69

69 70

70 71

71 72

72 73

73 74

74 75

75 76

76 77

77 78

78 79

79 80

80 81

81 82

82 83

83 84

84 85

85 86

86 87

87 88

88 89

89 90

90 91

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

In one embodiment, provided herein is a compound of formula I selected from the group consisting of:

-   5a-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,     6-hexahydrocyclopropa[f]indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,5′,7′-tetrahydrospiro[cyclopropane-1,6′-indazole]-3′-carboxamide; -   5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)-4,5,6,     7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; -   N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-phenyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl)-1,4,     5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide; -   5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,7-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl)-5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide; -   6-methyl-N—((S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl)-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxamide; -   6-methyl-N—((S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; -   (R)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)-2-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide; -   5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,6,7-tetrahydroindazole-3-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide; -   6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6, 8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1H-pyrazol-1-yl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   1-ethyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-4-carboxamide; -   1-ethyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   (S)-1,1-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)-5,     5-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide; -   (S)-6,6-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide; -   5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,     2,4-triazole-3-carboxamide; -   (S)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,     6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-5,     6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl)-5,     6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; -   (S)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (R)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,     5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydro-2H-indazole-3-carboxamide; -   N—((S)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide; -   5-(tert-butyl)-N—((S)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,     5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide; -   (S)—N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide; -   N—((S)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroquinoline-2-carboxamide; -   (S)-6-chloro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[,2,4]triazolo[4,3-b]pyridazine-3-carboxamide; -   (S)—N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3,4,5,     5a,6,6a-hexahydrocyclopropa[e]indazole-1-carboxamide; -   (S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide; -   5-methyl-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)-5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3,4,     5,5a,6,6a-hexahydrocyclopropa[e]indazole-1-carboxamide; -   (R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (R)-5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,     6,7-tetrahydro-1H-indazole-3-carboxamide; -   5-methyl-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; -   5-methyl-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   5-(tert-butyl)-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   (S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   (S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; -   (R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   (R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide: -   1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide; -   (S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-(trifluoromethyl)     imidazo[1,5-a]pyridine-1-carboxamide; -   N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-(trifluoromethyl)     imidazo[1,5-a]pyridine-1-carboxamide; -   (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)-5-chloro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide; -   (S)-5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)-5-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,     7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,     2,4]triazolo[4,3-b]pyridazine-3-carboxamide; and -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,     2,4]triazolo[4,3-a]pyridine-3-carboxamide.

In one embodiment, provided herein is a compound of formula I selected from the group consisting of:

-   5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-phenyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide; -   5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,7-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl)-5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide; -   6-methyl-N—((S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; -   (R)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,6,7-tetrahydroindazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1H-pyrazol-1-yl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   1-ethyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   (S)-1,1-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,     2,4-triazole-3-carboxamide; -   (S)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-5,     6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl)-5,     6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; -   (R)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetra hydro-2H-indazole-3-carboxamide; -   N—((S)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-methyl-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide; -   5-(tert-butyl)-N—((S)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4,     5,6,7-tetra hydro-1H-indazole-3-carboxamide; -   (S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide; -   5-methyl-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)-5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (R)-5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,     6,7-tetrahydro-1H-indazole-3-carboxamide; -   5-methyl-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; -   5-methyl-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   5-(tert-butyl)-N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; -   5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   (S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   (S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; -   (R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide; -   (R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide; -   1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydro-2H-indazole-3-carboxamide; -   (S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-(trifluoromethyl)     imidazo[1,5-a]pyridine-1-carboxamide; -   N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-(trifluoromethyl)     imidazo[1,5-a]pyridine-1-carboxamide; -   (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)-5-chloro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide; -   (S)-5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)-5-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,     7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,     2,4]triazolo[4,3-b]pyridazine-3-carboxamide; and -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,     2,4]triazolo[4,3-a]pyridine-3-carboxamide.

In another embodiment, provided herein is a compound selected from the compounds of Tables 1, 2, 3, 4 and 5 below. In one embodiment, the compound is a compound of Table 1. In another embodiment, the compound is a compound of Table 2.

In one embodiment, provided herein is a compound selected from the group consisting of:

-   (S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,     5,6,7-tetrahydro-2H-indazole-3-carboxamide; -   (S)-5-chloro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide; -   (S)-5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)-5-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,     7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)—N—((S)-6,     8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,     5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; -   (S)-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]isothiazole-3-carboxamide; -   (S)-1-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,     7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide; -   (S)-5-(4-fluorobenzyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)-5-(2,3-difluorobenzyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   1-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-1H-1,     2,4-triazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(perfluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-1H-indazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4′H,6′H-spiro[cyclopentane-1,5′-pyrrolo[1,2-c][1,2,3]triazole]-3′-carboxamide; -   (S)-1-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide; -   (S)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide; -   (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-b]pyridine-3-carboxamide; -   1-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-5-chloro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-b]pyridine-3-carboxamide; -   1-benzyl-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   1-benzyl-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,     6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide; -   (S)-1-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide; -   N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide; -   (S)-1-benzyl-N-(4-methyl-5-oxo-4,     5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,6-hexahydroimidazo[1,5-a][1,3]diazocin-3-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(cyclopentylmethyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (R)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   (S)-1-(cyclopentylmethyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(cyclohexylmethyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((S)-1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxamide; -   (S)-1-(4-chlorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   6-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,     2,3]triazolo[1,5-a]pyridine-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxamide; -   (S)-1-ethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide; -   5-(2,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide; -   5-(2,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide; -   (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide; -   (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxamide; -   (S)-1-(2,3-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(3,4-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(2,4-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide; -   1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl)imidazo[1,5-c]pyrimidine-1-carboxamide; -   (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide; -   (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-ethyl-1-meth     yl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(,     1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide; -   1-cyclopropyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-(4-fluorophenyl)ethyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(2,3-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,     3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(3,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,     3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-benzyl-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-4,5,     6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide; -   (S)-1-(2,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,     3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(4-fluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrarazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   1-(4-chlorobenzyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide; -   (S)-1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2′,3′,5′,6′-tetrahydro-3H-spiro[furo[3,4-c]pyridine-1,4′-pyran]-6-carboxamide; -   (S)-5-benzyl-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,6-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)-1-(2,5-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,3-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide; -   7-ethyl-7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide; -   1-(2,3-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   1-(2,4-difluorobenzyl)-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   1-(2,4-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide; -   1-(2,3-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   1-(3,4-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   1-(2,4-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide; -   N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,     6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;     and -   (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxamide.

SYNTHESIS

Compounds of formula I may be prepared by the processes illustrated in the schemes below or by methods known to those of ordinary skill in the art. Scheme 1 below is an example of a method of preparing a compound of formula I, wherein “R” represent the “right-hand side” building block derived from the carboxylic acid intermediates of exemplary Schemes 2-14 and 26-35 (when L of formula I is absent) or is as prepared according to the procedures described in WO 2014/125444 (wherein L is present). Schemes 15-25 show illustrative methods for making the “left-hand side” lactam building blocks of compounds of formulae I, I(a) and I(b).

Isothiazoles are prepared in the same way shown in Scheme 11 by substituting NH₂—OH for NH₂—SH.

Pharmaceutical Compositions and Administration

Provided herein are pharmaceutical compositions or medicaments containing the compounds of the invention (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof), and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula I are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. In some embodiments, the “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit RIP1 kinase activity in order to provide a therapeutic effect in the mammal being treated. In addition, such an effective amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

In one example, the pharmaceutically effective amount of the compound of the invention administered intravenously or parenterally will be in the per dose range of about 0.1 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, or alternatively about 0.3 to 15 mg/kg/day.

In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 1 to about 1000 mg (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg) of the compound of the invention. The daily does is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

In some embodiments, a low dose of the compound of the invention is administered in order to provide therapeutic benefit while minimizing or preventing adverse effects.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In specific embodiments, the compound of formula I is administered orally. In other specific embodiments, the compound of formula I is administered intravenously.

The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). A active pharmaceutical ingredient of the invention (e.g., compound of formula I or an embodiment thereof) can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams & Wilkins, Philidelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g., compound of formula I or an embodiment thereof) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposomally entrapped compounds, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamelar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal therapy.

In one example, compounds of formula I or an embodiment thereof may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula I (or an embodiment thereof) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula I or an embodiment thereof are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

An example of a suitable oral dosage form provided herein is a tablet containing about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg) of the compound of the invention compounded with suitable amounts of anhydrous lactose, sodium croscarmellose, polyvinylpyrrolidone (PVP) K30, and magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.

Formulations of a compound of the invention (e.g., compound of formula I or an embodiment thereof) can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans can contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.

The formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula I, or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

When the binding target is located in the brain, certain embodiments of the invention provide for a compound of formula I (or an embodiment thereof) to traverse the blood-brain barrier. In these embodiments, the compounds provided herein exhibit sufficient brain penetration as potential therapeutics in neurological diseases. In some embodiments, brain penetration is assessed by evaluating free brain/plasma ratio (B_(u)/P_(u)) as measured in vivo pharmacokinetic studies in rodents or by other methods known to persons skilled in the art (see, e.g., Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008).

Certain neurological diseases are associated with an increase in permeability of the blood-brain barrier, such that a compound of formula I (or an embodiment thereof) can be readily introduced to the brain. When the blood-brain barrier remains intact, several art-known approaches exist for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods. Physical methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, circumventing the blood-brain barrier entirely, or by creating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion/convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080, 1994), and implanting a delivery device in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Methods of creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002/0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating the a compound of formula I or I-I (or an embodiment thereof) in liposomes that are coupled to antibody binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Publication No. 2002/0025313), and coating a compound of formula I (or an embodiment thereof) in low-density lipoprotein particles (see, e.g., U.S. Patent Publication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S. Patent Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase permeability of the blood-brain barrier (see, e.g., U.S. Patent Publication Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. Patent Publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Publication No. 2003/0073713); coating a compound of formula I or I-I (or an embodiment thereof) with a transferrin and modulating activity of the one or more transferrin receptors (see, e.g., U.S. Patent Publication No. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat. No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can be administered continuously by infusion into the fluid reservoirs of the CNS, although bolus injection may be acceptable. The inhibitors can be administered into the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration can be performed by use of an indwelling catheter and a continuous administration means such as a pump, or it can be administered by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitors can be injected through chronically implanted cannulas or chronically infused with the help of osmotic minipumps. Subcutaneous pumps are available that deliver proteins through a small tubing to the cerebral ventricles. Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving a subcutaneous pump device or continuous intracerebroventricular infusion through a totally implanted drug delivery system are those used for the administration of dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models for Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143, 1987.

Indications and Methods of Treatment

The compounds of the invention inhibit RIP1 kinase activity. Accordingly, the compounds of the invention are useful for the treatment of diseases and disorders mediated by this pathway and associated with inflammation and/or necroptotic cell death. Compounds of the invention are therefore useful for the treatment or prevention of a disease or disorder selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cysplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

In another embodiment, compounds of the invention are useful for the treatment of one or more symptoms of the above diseases and disorders. In some embodiments, the disease or disorder is an irritable bowel disorder. In some embodiments, the disease or disorder is irritable bowel syndrome (IBS), Crohn's disease, or ulcerative colitis. In some embodiments, the disease or disorder is an ischemia-reperfusion injury of kidneys, liver and lungs. In some embodiments, the disease or disorder is a chronic kidney disease. In some embodiments, the disease or disorder is acute respiratory distress syndrome (ARDS). In some embodiments, the disease or disorder is chronic obstructive pulmonary disease (COPD).

In some embodiments, the disease or disorder to be treated is selected from the group consisting of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, liver damage/diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury(AKI)), Celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atropy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency ((also known as RBCKI) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as tuberculosis and influenza), and Lysosomal storage diseases (particularly, Gaucher Disease, and including GM2, Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, Cholesteryl Ester storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease, Farber disease, Fucosidosis, Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Infantile Free Sialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Metachromatic Leukodystrophy, Mucopolysaccharidoses disorders, Multiple sulfatase deficiency, Niemann-Pick Disease, Neuronal Ceroid Lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease, Schindler disease, Sialic Acid Storage Disease, Tay-Sachs and Wolman disease).

Also provided herein is the use of a compound of the invention in therapy. In some embodiments, provided herein is the use of a compound of the invention for the treatment or prevention of the above diseases and disorders. Also provided herein is the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of the above diseases and disorders.

Also provided herein is a method of treating a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cysplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD), wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of treating a symptom of a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (B S), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cysplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD), wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of treating a disease or disorder in a mammal in need of such treatment, said disease or disorder being selected from the group consisting of irritable bowel disorders (IBD), irritable bowel syndrome (B S), Crohn's disease, and ulcerative colitis, wherein the method comprises orally administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as an orally acceptable pharmaceutical composition.

Combination Therapy

Compounds of the invention may be combined with one or more other compounds of the invention or one or more other therapeutic agent as any combination thereof, in the treatment of the diseases and disorders provided herein. For example, a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents known to be useful for the treatment of a disease or disorder selected from those recited above.

In some embodiments, a compound provided herein may be combined with another therapeutically active agent as recited in WO 2016/027253, the contents of which are hereby incorporated by reference in their entirety. In such embodiments, the compound that inhibits RIP1 kinase in the combinations recited in WO 2016/027253 is replaced by a compound of formula I of the present disclosure.

As used herein “combination” refers to any mixture or permutation of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agent. Unless the context makes clear otherwise, “combination” may include simultaneous or sequentially delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, “combination” may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include formulations of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein.

EXAMPLES

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

These examples serve to provide guidance to a skilled artisan to prepare and use the compounds, compositions and methods of the invention. While particular embodiment of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the inventions.

The chemical reactions in the examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully performed by modifications apparent to those skilled in the art, for example, by appropriately protecting interfering group, by utilizing other suitable reagents known in the art, for example, by appropriately protecting interfering groups by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions.

In the examples below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Commercially available reagents were purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and were used without further purification unless otherwise indicated. The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO, CH₃OD or d₆-acetone solvent solutions (reported in ppm) using or trimethylsilane (TMS) or residual non-deuterated solvent peaks as the reference standard. When peak multiplicities are reported, the following abbreviates are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hz (Hertz).

In the examples below, LCMS methods were performed for 10 or 30 minutes according to the following conditions:

Agilent 10 min LCMS Method: Experiments performed on an Agilent 1290 UHPLC coupled with Agilent MSD (6140) mass spectrometer using ESI as ionization source. The LC separation was using a Phenomenex XB-C18, 1.7 mm, 50×2.1 mm column with a 0.4 ml/minute flow rate. Solvent A is water with 0.1% FA and solvent B is acetonitrile with 0.1% FA. The gradient consisted with 2-98% solvent B over 7 min and hold 98% B for 1.5 min following equilibration for 1.5 min. LC column temperature is 40° C. UV absorbance was collected at 220 nm and 254 nm and mass spec full scan was applied to all experiment.

Agilent 30 min LCMS Method: Experiments performed on an Agilent 1100 HPLC coupled with Agilent MSD mass spectrometer using ESI as ionization source. The LC separation was using an Agilent Eclipse XDB-C18, 3.5 mm, 100×3.0 mm column with a 0.7 ml/minute flow rate. Solvent A is water with 0.1% FA and solvent B is acetonitrile with 0.1% FA. The gradient consisted with 2-98% solvent B over 25.5 min and hold 98% B for 2.5 min following equilibration for 1.5 min. UV absorbance were collected at 220 nm and 254 nm and mass spec full scan was applied to all experiment.

All abbreviations used to describe reagents, reaction conditions or equipment are intended to be consistent with the definitions set forth in the following list of Abbreviations.

The chemical names of discrete compounds of the invention were typically obtained using the structure naming feature of ChemDraw naming program.

ABBREVIATIONS ACN Acetonitrile

Boc tert-Butoxycarbonyl

DMF N,N-Dimethylformamide

DMSO Dimethyl sulfoxide

HPLC High Pressure Liquid Chromatography LCMS Liquid Chromatography Mass Spectrometry

RP Reverse phase RT or R_(T) Retention time

SEM 2-(Trimethylsilyl)ethoxymethyl THF Tetrahydrofuran Preparative Examples Example 1 Synthetic Method A

According to synthetic Method A, 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid and similar carboxylic acid systems are prepared according to the paragraph below or from procedures described in J. Med. Chem. (2014), 57(13), 5714-5727; J Med. Chem. (2015), 58(9), 3806-3816; and WO 2014023258 A1.

Step 1: 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid

To a stirred solution of ethyl 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylate (200 mg, 0.907 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added a solution of 2M LiOH (0.69 mL, 1.36 mmol), and stirred at RT for 16 h. The reaction mixture was concentrated to dryness in vacuo, redissolved in water and neutralized with 1N HCl. The resulting crashed out solid was filtered, wash with water and dried affording 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid (120 mg, 69% yield) used in the next step without any further purification.

Step 2: 5a-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5, 5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide

To a screw cap vial 5a-methyl-4,4a,5,6-tetrahydro-1H-cyclopropa[f]indazole-3-carboxylic acid (20 mg, 0.104 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (51 mg, 0.1357), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one hydrochloride (26 mg, 0.115 mmols) was added and dissolved in N,N-dimethylformamide (3 mL). To the reaction mixture was added trimethylamine (0.101 mL, 0.728 mmol), the vial was capped and stirred at RT for 16 h. The mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording 5a-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a, 6-hexahydrocyclopropa[f]indazole-3-carboxamide (12 mg, 31%): ¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.96-7.87 (m, 1H), 7.52-7.44 (m, 1H), 7.35-7.26 (m, 2H), 7.25-7.21 (m, 1H), 4.88-4.75 (m, 1H), 4.53-4.44 (m, 1H), 4.43-4.36 (m, 1H), 3.11-3.02 (m, 1H), 2.98-2.90 (m, 1H), 2.79-2.70 (m, 1H), 2.70-2.60 (m, 1H), 1.19 (s, 3H), 1.03-0.93 (m, 1H), 0.35-0.26 (m, 1H), 0.09-0.00 (m, 1H). LC-MS R_(T)=4.98 min, m/z=367.2 (M+H)⁺.

Example 2 Method A′

Step 1: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,5′,7′-tetrahydrospiro[cyclopropane-1,6′-indazole]-3′-carboxamide

To a solution of 1′-((2-(trimethylsilyl)ethoxy)methyl)-1′,4′,5′,7′-tetrahydrospiro[cyclopropane-1,6′-indazole]-3′-carboxylic acid (68 mg, 0.21 mmol) in N,N-dimethylformamide (0.350 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (40 mg, 0.21 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (86 mg, 1.3527 mmol) and triethylamine (0.171 mL, 0.0012 mmol) and stirred at RT for 16 h. The residue was dissolved in methanol (2 mL) and a 4M solution of HCl in dioxane (0.135 mL, 3.66 mmol,). The reaction mixture was stirred at RT for 16 h, concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,5′,7′-tetrahydrospiro[cyclopropane-1,6′-indazole]-3′-carboxamide (9 mg, 12% yield): ¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 1H), 7.35-7.26 (m, 2H), 7.25-7.21 (m, 1H), 4.90-4.76 (m, 1H), 4.56-4.32 (m, 2H), 2.68-2.55 (m, 2H), 2.48-2.42 (m, 2H), 1.53-1.37 (m, 2H), 0.42-0.33 (m, 4H). LC-MS R_(T)=4.64 min, m/z=367.2 (M+H)⁺.

Example 3 Method B

According to synthetic Method B, 5-(tert-butyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid and similar carboxylic acid systems are prepared according to the paragraph below or from procedures described in J. Med. Chem. (2014), 57(13), 5714-5727; J. Med. Chem. (2015), 58(9), 3806-3816; and WO 2014023258 A1.

5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a screw cap vial (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one hydrochloride (30 mg, 0.131 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (75 mg, 0.197 mmol), 5-(tert-butyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (35 mg, 0.157 mmols) was added and dissolved in N,N-dimethylformamide (5 mL). To the reaction mixture was added trimethylamine (0.127 mL, 0.918 mmol), the vial was capped and stirred at RT for 16 h. The mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording 5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4, 5,6,7-tetrahydro-1H-indazole-3-carboxamide

(9 mg, 14%): ¹H NMR (400 MHz, DMSO-d6) δ 12.88-12.77 (m, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.51-7.46 (m, 1H), 7.35-7.26 (m, 2H), 7.27-7.19 (m, 1H), 4.88-4.77 (m, 1H), 4.55-4.35 (m, 2H), 2.86-2.65 (m, 2H), 2.19-2.05 (m, 1H), 2.01-1.91 (m, 1H), 1.37-1.17 (m, 2H), 0.89 (s, 9H). LCMS R_(T)=5.52 min, m/z=397.2 [M+H]⁺.

Example 4 Method B′

Step 1: N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide

To a screw cap vial 1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid (44 mg, 0.247 mmol), 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate (127 mg, 0.3367 mmol), 3S)-3-amino-3,5-dihydro-2H-1,5-benzoxazepin-4-one (40 mg, 0.225 mmol) was added and dissolved in N,N-dimethylformamide (3 mL). To the reaction mixture was added trimethylamine (0.094 mL, 0.673 mmol), the vial was capped and stirred at RT for 16 h. The mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording

N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide (10.4 mg, 14%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.12 (s, 1H), 8.02-7.87 (m, 1H), 7.22-7.05 (m, 4H), 4.87-4.66 (m, 1H), 4.55-4.32 (m, 2H), 3.23-3.09 (m, 1H), 3.00-2.62 (m, 4H), 2.15-2.01 (m, 1H), 1.32-1.09 (m, 2H), 0.62-0.40 (m, 1H), −0.05-−0.14 (m, 1H). LCMS R_(T)=4.21 min, m/z=339.1 [M+H]⁺.

Example 5 Method C

According to synthetic Method C, 5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxylic acid and similar carboxylic acid systems are prepared according to the paragraph below or from procedures described in J. Med. Chem. (2014), 57(13), 5714-5727; J. Med. Chem. (2015), 58(9), 3806-3816; and WO 2014023258 A1.

Step 1: tert-butyl (S)-3-((5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamoyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of 5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (455 mg, 1.15 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (200 mg, 1.0405 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (524.83 mg, 1.3527 mmol) and N,N-diisopropylethylamine (1.27 mL, 7.2837 mmol) and stirred at RT for 16 h. To the reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to afford tert-butyl (S)-3-((5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamoyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (523 mg, 88%) as a colorless oil: LCMS R_(T)=1.62 min, m/z=572.1 [M+H]⁺.

Step 2: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide hydrochloride

To a stirred solution of tert-butyl 3-[[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]carbamoyl]-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (523 mg, 0.915 mmol) in methanol was added a 4M solution of HCl in dioxane (0.915 mL, 3.66 mmol). The reaction mixture was stirred at RT for 16 h and concentrated to dryness in vacuo to afford crude (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide hydrochloride (317 mg, 92%) used in the next step without further purification: LCMS R_(T)=0.77 min, m/z=342.1 [M+H]⁺.

Step 3: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a stirred solution of N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide hydrochloride (30 mg, 0.07941 mmol) in dichloromethane was added N,N-diisopropylethylamine (0.0416 mL., 0.2382 mmol). To the reaction mixture was added 2,2,2-trifluoroethyltrifluoromethanesulphonate (24.70 mg, 0.1032 mmol) and was stirred at 35° C. for 16 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (13 mg, 38%) as a white solid:

¹H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.48 (dd, J=7.7, 1.8 Hz, 1H), 7.35-7.26 (m, 2H), 7.23 (dd, J=7.7, 1.8 Hz, 1H), 4.87-4.75 (m, 1H), 4.58-4.47 (m, 1H), 4.44-4.35 (m, 1H), 3.74 (s, 2H), 2.89 (t, J=5.7 Hz, 2H), 2.69 (t, J=5.6 Hz, 2H).

Example 6 Method D

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-phenyl-4,6,7,8-tetrahydro pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1: tert-butyl 2-[[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate

To a solution of 5-tert-butoxycarbonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (500 mg, 1.78 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (376 mg, 1.96 mmol) 1-hydroxybenzotriazole (288 mg, 2.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (409 mg, 2.13 mmol). The reaction mixture was stirred at RT for 2 h and then diluted with ethyl acetate (15 mL). The solution was washed with water (3×15 mL), brine (3×15 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford tert-butyl 2-[[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (800 mg, 99% yield) as a light yellow oil: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.72 min, ESI+ found [M+H]=456.

Step 2: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 2,2,2-trifluoroacetate

To a solution of tert-butyl 2-[[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (780 mg, 1.71 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at RT for 2 h and then concentrated to dryness in vacuo affording N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 2,2,2-trifluoroacetate (802 mg, 100% yield) as a yellow solid used as is in the next step: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.29 min, ESI+ found [M+H]=356.

Step 3: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-phenyl-4,6,7,8-tetrahydro pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a mixture of N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 2,2,2-trifluoroacetate (197 mg, 0.42 mmol) in toluene (5 mL) was added copper(II) acetate (8 mg, 0.04 mmol), tetradecanoic acid (19 mg, 0.08 mmol), 2,6-lutidine (45 mg, 0.42 mmol) and phenylboronic acid (77 mg, 0.63 mmol) under oxygen (15 Psi). The reaction mixture was stirred at 25° C. for 12 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (0-40% acetonitrile in water and 0.1% ammonium hydroxide) affording N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-phenyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.5 mg, 1.4% yield) as white solid: ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J=8.0 Hz, 1H), 7.51-7.44 (m, 1H), 7.35-7.18 (m, 3H), 7.10 (t, J=8.0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.73 (s, 1H), 6.58 (t, J=7.2 Hz, 1H), 4.83-4.64 (m, 3H), 4.54-4.40 (m, 3H), 4.37-434 (m, 1H), 3.93-3.79 (m, 2H), 3.29 (s, 3H), 1.84-1.82 (m, 2H).

LCMS R_(T)=2.45 min, m/z=432.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 2.45 min, ESI+ found [M+H]=432.2.

Example 7 Method E

5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide and 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide Step 1

Ethyl 2-diazo-2-(4-hydroxy-2-methyltetrahydro-2H-pyran-4-yl) acetate

To a solution of ethyl 2-diazoacetate (8.0 g, 70.1 mmol) and 2-methyldihydro-2H-pyran-4(3H)-one (5.0 g, 43.8 mmol) in tetrahydrofuran (100 mL) was added lithium diisopropylamide (2 M in tetrahydrofuran, 39.5 mL, 79.0 mmol) at −78° C. under nitrogen. After addition, the reaction mixture was stirred at −78° C. for 1 h and then quenched by addition of saturated aqueous ammonium chloride (60 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford ethyl 2-diazo-2-(4-hydroxy-2-methyl-tetrahydropyran-4-yl)acetate (4.0 g, 40% yield).

Step 2: Ethyl 5-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate and ethyl 7-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a solution of ethyl 2-diazo-2-(4-hydroxy-2-methyl-tetrahydropyran-4-yl)acetate (3.0 g, 13.1 mmol) in pyridine (20 mL) was added phosphorus oxychloride (8.06 g, 52.6 mmol). The resulting mixture was stirred at 15° C. for 3 h and then poured into water (20 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25% ethyl acetate in petroleum ether) to afford a mixture of regio-isomer, which was further purified by RP-HPLC (15-45% acetonitrile in water and 0.05% ammonia) to afford ethyl 5-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (300 mg, 10.9% yield) and ethyl 7-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (300 mg, 1.427 mmol, 10.9% yield) as white solids.

Step 3: 5-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid

To a solution of ethyl 5-methyl-2,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (100 mg, 0.48 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide monohydrate (320 mg, 7.61 mmol). The reaction mixture was stirred at 15° C. for 15 h and then concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and then adjusted to pH=3 by adding 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3×15 mL). The combined layers were dried over anhydrous sodium sulfate and concentrated to afford 5-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (80 mg, 92.3% yield) as a white solid, which was used into next step without further purification.

Step 4: 5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (60 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (50 mg, 0.37 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (72 mg, 0.37 mmol) and 5-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (63 mg, 0.34 mmol). The reaction mixture was stirred at 15° C. for 1 h and then concentrated to dryness in vacuo. The residue was purified by RP-HPLC (28-58% acetonitrile in water and 0.05% hydrochloric acid) to afford 5-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (55.7 mg, 49% yield) as a white solid: ¹H NMR (400 MHz, Methanol-d4) δ 7.44-7.40 (m, 1H), 7.35-7.26 (m, 2H), 7.25-7.20 (m, 1H), 5.01-4.97 (m, 1H), 4.82-4.77 (m, 1H), 4.72-4.70 (m, 1H), 4.61-4.57 (m, 1H), 4.41-4.33 (m, 1H), 3.70-3.66 (m, 1H), 3.41 (s, 3H), 2.87-2.82 (m, 1H), 2.50-2.44 (m, 1H), 1.32 (d, J=6.0 Hz, 3H). LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.77 min, ESI+ found [M+H]=357.0.

Step 5: 7-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid

To a solution of ethyl 7-methyl-1,4,5,7-tetrahydropyrano[3,4-c]hpyrazole-3-carboxylate (100 mg, 0.48 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide monohydrate (320 mg, 7.61 mmol). The reaction mixture was stirred at 15° C. for 15 h and then concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and then adjusted to pH=3 by adding 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3×15 mL). The combined layers were dried over anhydrous sodium sulfate and concentrated to afford 7-methyl-1,4,5,7-tetrahydropyrano[3,4-c]hpyrazole-3-carboxylic acid (˜80 mg, 92.3% yield) as a white solid used in the next step without further purification.

Step 6: 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (60 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (50 mg, 0.37 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (72 mg, 0.37 mmol) and 7-methyl-2,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (63 mg, 0.34 mmol). The reaction mixture was stirred at 15° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (25-48% acetonitrile in water and 0.05% hydrochloric acid) to afford 7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-2,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (39.8 mg, 35% yield) as a white solid: ¹H NMR (400 MHz, Methanol-d4) δ 7.44-7.40 (m, 1H), 7.35-7.26 (m, 2H), 7.25-7.20 (m, 1H), 4.99-4.91 (m, 1H), 4.77-4.75 (m, 1H), 4.62-4.56 (m, 1H), 4.41-4.33 (m, 1H), 4.19-4.12 (m, 1H), 3.62-3.60 (m, 1H), 3.41 (s, 3H), 2.80-2.73 (m, 1H), 1.47 (d, J=6.8 Hz, 3H). LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.76 min, ESI+ found [M+H]=357.0.

Example 8 Method F

(S)-5,5-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5, 7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

and

(S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2,4,5, 7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

Step 1: Ethyl 2-diazo-2-(4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl) acetate

To a solution of 2,2-dimethyl tetrehydropyran-4-one (5.0 g, 39.0 mmol) and ethyl diazoacetate (7.1 g, 62.4 mmol) in tetrahydrofuran (100 mL) was added lithium diisopropylamide (2 M in tetrahydrofuran, 35.1 mL, 70.2 mmol) at −78° C. under nitrogen. After addition, the reaction mixture was stirred at −78° C. for 1 h and then quenched by addition of saturated aqueous ammonium chloride (60 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford ethyl 2-diazo-2-(4-hydroxy-2, 2-dimethyl-tetrahydropyran-4-yl) acetate (6.0 g, 63.5% yield) as a yellow oil use as is in the next step.

Step 2: ethyl 5,5-dimethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate and ethyl 7,7-dimethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a solution of ethyl 2-diazo-2-(4-hydroxy-2, 2-dimethyl-tetrahydropyran-4-yl) acetate (3.0 g, 12.38 mmol) in pyridine (60 mL) was added phosphorus oxychloride (7.6 g, 49.53 mmol). The reaction mixture was stirred at 15° C. for 3 h and then poured into water (30 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25% ethyl acetate in petroleum ether) to afford a mixture of ethyl 7,7-dimethyl-4,5-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxylate and ethyl 7,7-dimethyl-4,5-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxylate (1.0 g, 36% yield, 1:1 mixture) as light yellow oil used as is in the next step: LCMS R_(T)=0.62 min, m/z=224.8 [M+H]⁺. LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.615 min, ESI+ found [M+H]=224.8.

Step 3: 5,5-dimethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid and 4,4-dimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid

To a solution of ethyl 5,5-dimethyl-4,7-dihydro-2H-pyrano[3,4-c]pyrazole-3-carboxylate and ethyl 7,7-dimethyl-4,5-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxylate (200 mg, 0.9 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (299 mg, 7.1 mmol). The reaction mixture was stirred at 15° C. for 15 h and concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and adjusted to pH=3 with 1M hydrochloric acid. The resulting mixture was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to afford a crude mixture of 5,5-dimethyl-4,7-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxylic acid and 7,7-dimethyl-4,5-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxylic acid (120 mg, 68.6% yield) as a yellow oil used in the next step without any further purification.

Step 4: (S)-5,5-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5, 7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (100 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL) was added a mixture of 5,5-dimethyl-4,7-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxylic acid and 7,7-dimethyl-4,5-dihydro-2H-pyrano[3,4-c]pyrazole-3-carboxylic acid (118 mg, 0.60 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (83 mg, 0.62 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (99 mg, 0.52 mmol). The reaction mixture was stirred at 15° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (17-37% acetonitrile in water and 0.05% ammonia hydroxide) to afford:

5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,7-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxamide (59 mg, 30.7% yield) as white solid: ¹H NMR (400 MHz, Methanol-d4) δ 7.44-7.40 (m, 1H), 7.35-7.26 (m, 2H), 7.25-7.20 (m, 1H), 5.01-4.97 (m, 1H), 4.71 (s, 2H), 4.62-4.57 (m, 1H), 4.39-4.36 (m, 1H), 3.42 (s, 3H), 2.68 (s, 2H), 1.25 (s, 6H). LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.79 min, ESI+ found [M+H]=371.0.

7,7-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5-dihydro-2H-pyrano[3,4-c]pyrazole-3-carboxamide (20 mg, 10.4% yield) as white solid: ¹H NMR (400 MHz, METHANOL-d4) δ 13.10 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.34-7.22 (m, 3H), 4.87-4.80 (m, 1H), 4.55-4.49 (m, 1H), 4.42-4.37 (m, 1H), 3.73 (s, 2H), 3.31 (s, 3H), 2.58-2.20 (m, 2H), 1.39 (s, 6H). LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.78 min, ESI+ found [M+H]=371.0.

Example 9 Method G

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

Step 1: Ethyl 5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a solution of 2-phenyltetrahydropyran-4-one (1.00 g, 5.68 mmol) in dimethyl sulfoxide (10 mL) was added ethyl diazoacetate (0.32 g, 2.84 mmol) and pyrrolidine (40.3 mg, 0.57 mmol) under nitrogen protection. The reaction mixture was stirred at RT for 12 h and diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (3×50 mL), brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl 5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (180 mg, 12% yield) as a light yellow oil: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.70 min, ESI+ found [M+H]=273.

Step 2: 5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid

To a solution of ethyl 5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (100 mg, 0.37 mmol) in ethanol (4 mL) and water (4 mL) was added lithium hydroxide monohydrate (154 mg, 3.67 mmol). The reaction mixture was stirred at RT for 12 h and concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and adjusted to pH=5 with 1M hydrochloric acid. The mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to afford 5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (89 mg, 99% yield) as yellow oil used in the next step without any further purification:

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.62 min, ESI+ found [M+H]=245.

Step 3: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

To a solution of 5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (88.0 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (58 mg, 0.43 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (83 mg, 0.43 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (76 mg, 0.40 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (0-40% acetonitrile in water and 0.1% ammonia hydroxide) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (24 mg, 16% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 13.10 (br. s, 1H), 8.04 (br. s, 1H), 7.47-7.23 (m, 9H), 4.97-4.92 (m, 1H), 4.85-4.82 (m, 2H), 4.60-4.54 (m, 2H), 4.46-4.35 (m, 1H), 3.33 (s, 3H), 3.05-3.01 (m, 1H), 2.68-2.56 (m, 1H). LCMS R_(T)=1.88 min, m/z=419 [M+H]⁺.

LCMS (10-80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.88/min, ESI+ found [M+H]=419.

Example 10 Method H

6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxamide

Step 1: (1-trityl-1H-imidazol-4-yl) methanol

To a solution of (1H-imidazol-4-yl) methanol (5.0 g, 51.0 mmol) and triethylamine (15.5 g, 152.9 mmol) in N,N-dimethylformamide (100 mL) was slowly added (chloromethanetriyl)tribenzene (15.6 g, 56.1 mmol). After addition, the reaction mixture was stirred at RT for 3 h and then poured into water (300 mL). The resulting solid was collected by filtration, washed with water (2×100 mL) and recrystallized with dioxane (300 mL) to afford (1-trityl-1H-imidazol-4-yl)methanol (9.8 g, 56% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6): δ7.43-7.39 (m, 9H), 7.29 (s, 1H), 7.10-7.08 (m, 6H), 6.72 (s, 1H), 4.89-4.86 (m, 1H), 4.33-4.32 (d, J=5.6 Hz, 2H).

Step 2: ethyl 2-((1-trityl-1H-imidazol-4-yl)methoxy)propanoate

To a solution of (1-trityl-1H-imidazol-4-yl)methanol (6.0 g, 17.6 mmol) in N,N-dimethylformamide (400 mL) was added sodium hydride (60%, 1.4 g, 35.2 mmol) portionwise. After addition, the reaction mixture was stirred at RT for 2 h and ethyl 2-bromopropanoate (6.4 g, 35.2 mmol) was added. The resulting mixture was stirred at RT for another 15 h and quenched by addition of aqueous saturated ammonium chloride (300 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl 2-((1-trityl-1H-imidazol-4-yl)methoxy)propanoate (2.0 g, 26% yield) as an orange oil: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) R_(T)=0.81 min, m/z=449.1 [M−C₂H₅+CH₃+Na]⁺.

Step 3: 2-((1-trityl-1H-imidazol-4-yl)methoxy)propan-1-ol

To a solution of ethyl 2-((1-trityl-1H-imidazol-4-yl)methoxy)propanoate (2.00 g, 4.54 mmol) in methanol (40 mL) was added sodium borohydride (0.86 g, 22.70 mmol) in small portions. After addition, the reaction mixture was stirred at 25° C. for 16 h and then quenched by addition of saturated aqueous ammonium chloride (40 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford crude 2-((1-trityl-1H-imidazol-4-yl)methoxy)propan-1-ol (1.30 g, 72% yield) as colorless oil used in the next step without any further purification:

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+Na]=421.1.

Step 4: 2-((1-trityl-1H-imidazol-4-yl)methoxy)propyl 4-methylbenzenesulfonate

To a solution of 2-((1-trityl-1H-imidazol-4-yl)methoxy)propan-1-ol (1.3 g, 3.26 mmol) and triethylamine (1.0 g, 9.79 mmol) in dichloromethane (20 mL) was added 4-methylbenzene-1-sulfonyl chloride (0.8 g, 3.91 mmol) in small portions. After addition, the mixture was stirred at RT for 15 h. The reaction was washed with saturated sodium bicarbonate (2×15 mL), dried over sodium sulfate and concentrated to dryness in vacuo to afford crude 2-((1-trityl-1H-imidazol-4-yl)methoxy)propyl 4-methylbenzenesulfonate (1.8 g, 99% yield) as a colourless oil used in the next step without any further purification: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.86 min, ESI+ found [M+H]=553.1.

Step 5: 2-((1H-imidazol-4-yl)methoxy)propyl 4-methylbenzenesulfonate 2,2,2-trifluoroacetate

A mixture of 2-((1-trityl-1H-imidazol-4-yl)methoxy)propyl 4-methylbenzenesulfonate (1.8 g, 3.26 mmol) in 2,2,2-trifluoroacetic acid (20 mL) was stirred at RT for 3 h and concentrated to dryness in vacuo to afford crude 2-((1H-imidazol-4-yl)methoxy)propyl 4-methylbenzenesulfonate (1.0 g, 99% yield) as a red oil used in the next step without any further purification: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.64 min, ESI+ found [M+H]=310.9.

Step 6: 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine

A mixture of 2-((1H-imidazol-4-yl)methoxy)propyl 4-methylbenzenesulfonate (1.0 g, 3.22 mmol) and cesium carbonate (3.2 g, 9.67 mmol) in N,N-dimethylformamide (20 mL) was heated at 80° C. for 15 h. After cooled, the mixture was poured into water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine (0.2 g, 46% yield) as a white solid:

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.19 min, ESI+ found [M+H]=139.1.

Step 7: ethyl 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxylate

To a solution of 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine (0.20 g, 1.45 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.70 g, 5.79 mmol) in acetonitrile (2 mL) at −40° C. was added ethyl chloroformate (0.24 g, 2.17 mmol). After addition, the reaction mixture was stirred at RT for 15 h and then concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford ethyl 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxylate (0.09 g, 30% yield) as a colorless oil: LCMS R_(T)=1.52 min, m/z=211.2 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.52 min, ESI+ found [M+H]=211.2.

Step 8: lithium 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxylate

To a solution of ethyl 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxylate (90 mg, 0.43 mmol) in ethanol (8 mL) and water (4 mL) was added lithium hydroxide hydrate (180 mg, 4.28 mmol). The mixture was stirred at RT for 1 h and concentrated to dryness in vacuo to afford lithium 6-methyl-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxylate (71 mg, 90.7% yield) as white solid used in the next step without further purification.

Step 9: 6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxamide

To a solution of lithium 6-methyl-6, 8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxylate (71 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (53 mg, 0.39 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (75 mg, 0.39 mmol). The mixture was stirred at 20° C. for 2 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (30-60% acetonitrile in water and 0.05% ammonium hydroxide) to afford 6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6,8-dihydro-5H-imidazo[5,1-c][1,4]oxazine-3-carboxamide (37 mg, 39% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6): δ 8.39-8.36 (m, 1H), 7.50-7.48 (m, 1H), 7.32-7.30 (m, 2H), 7.29-7.24 (m, 1H), 6.89 (s, 1H), 4.99-4.95 (m, 1H), 4.78-4.73 (m, 2H), 4.60-4.56 (m, 2H), 4.52-4.39 (m, 1H), 3.84-3.83 (m, 1H), 3.65-3.62 (m, 1H), 3.31 (s, 3H), 1.23 (d, J=6.4 Hz, 3H). LCMS R_(T)=1.21 min, m/z=357.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid 2 mins) retention time 1.21 min, ESI+ found [M+H]=357.2.

Example 11 Method I

6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide

Step 1: ethyl 2-(((5-methylpyridin-2-yl)methyl)amino)-2-oxoacetate

A solution of (5-methylpyridin-2-yl)methanamine (1.00 g, 8.19 mmol) and triethylamine (1.24 g, 12.28 mmol) in tetrahydrofuran (10 mL) was added ethyl oxalyl chloride (1.23 g, 9.00 mmol) at 0° C. After addition, the reaction mixture was stirred at 20° C. for 10 h and then quenched with saturated aqueous sodium carbonate (20 mL). The solution was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl 2-[(5-methyl-2-pyridyl)methylamino]-2-oxo-acetate (1.20 mg, 66% yield) as brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1H), 8.19 (br., s, 1H), 7.46-7.44 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.56 (d, J=5.2 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).

Step 2: ethyl 6-methylimidazo[1,5-a]pyridine-3-carboxylate

A mixture of ethyl 2-[(5-methyl-2-pyridyl)methylamino]-2-oxo-acetate (1.0 g, 4.5 mmol) and phosphorus oxychloride (28.0 g, 182.6 mmol) was heated at 100° C. for 10 h and concentrated to dryness in vacuo. The residue was poured into water (20 mL) and adjusted to pH=8 by adding aqueous saturated sodium bicarbonate (20 mL). The resulting solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 70% ethyl acetate in petroleum ether) to afford ethyl 6-methylimidazo[1,5a]pyridine-3-carboxylate (250 mg, 27.2% yield) as brown solid: LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 1.5 mins) retention time: 0.74 min, ESI+ found [M+H]=204.8.

Step 3: ethyl 6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

A solution of ethyl 6-methylimidazo[1,5-a]pyridine-3-carboxylate (200 mg, 0.98 mmol) in methanol (5 mL) was treated with 10% palladium on carbon (200 mg, 0.19 mmol). The mixture was hydrogenated (50 psi) at 20° C. for 24 h and then filtered through Celite. The filtrate was concentrated to dryness in vacuo to afford the crude ethyl 6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (200 mg, 98.1% yield) as colorless oil used in the next step without any further purification: ¹H NMR (400 MHz, CDCl₃) δ 6.93 (s, 1H), 4.75-4.70 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.68-3.62 (m, 1H), 2.99-2.94 (m, 1H), 2.77-2.75 (m, 1H), 1.96-1.93 (m, 2H), 1.47-1.40 (m, 4H), 1.13 (d, J=6.8 Hz, 3H).

Step 4: 6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide

To a stirred solution of ethyl 6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (300 mg, 1.4 mmol) in ethanol (10 mL) and water (5 mL) was added lithium hydroxide (345 mg, 14.4 mmol). The mixture was stirred at 20° C. for 1 h and concentrated to dryness in vacuo pressure to afford crude lithium 6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate.

To a solution of crude lithium 6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (70 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (53 mg, 0.39 mmol) and N-1-((ethylamine)ethylene)-N₃,N₃-dimethylpropane-1,3-diamine hydrochloride (75 mg, 0.39 mmol). The mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (49% acetonitrile in water and 0.05% ammonia hydroxide) to afford 6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide (29 mg, 31.4% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 8.28-8.25 (m, 1H), 7.50-7.47 (m, 1H), 7.34-7.29 (m, 2H), 7.24-7.23 (m, 1H), 6.82 (s, 1H), 4.82-4.75 (m, 1H), 4.58-4.51 (m, 2H), 4.42-4.40 (m, 1H), 3.55-3.49 (m, 1H), 3.31 (s, 3H), 2.86-2.85 (m, 1H), 2.72-2.64 (m, 1H), 2.53-2.51 (m, 1H), 1.83-1.80 (m, 1H), 1.38-1.32 (m, 1H), 0.99 (d, J=6.4 Hz, 3H). LCMS (10 to 80% acetonitrile in water+0.1% NH4OH over 3 mins) retention time 1.90 min, ESI+ found [M+H]=355.2.

Example 12 Method J

N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

Step 1: ethyl 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

To a solution of 4-phenylcyclohexanone (2.0 g, 11.48 mmol) in dimethyl sulfoxide (20 mL) was added pyrrolidine (40.8 mg, 0.57 mmol). The mixture was stirred at 20° C. for 15 min, and ethyl 2-diazoacetate (654.8 mg, 5.74 mmol) was added. The resulting mixture was stirred at 20° C. for 15 h and then diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 25% ethyl acetate in petroleum ether) to afford ethyl 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (830 mg, 53% yield) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.32 (m, 2H), 7.27-7.22 (m, 3H), 4.39-4.33 (m, 2H), 3.08-2.97 (m, 3H), 2.81-2.72 (m, 2H), 2.15-2.12 (m, 1H), 1.95-1.89 (m, 1H), 1.38-1.34 (m, 3H).

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.99 min, ESI+ found [M+H]=271.2.

Step 2: 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

To a solution of ethyl 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (400 mg, 1.5 mmol) in tetrahydrofuran (8 mL) and water (8 mL) was added lithium hydroxide monohydrate (354 mg, 14.8 mmol). The mixture was stirred at 20° C. for 22 h and concentrated to dryness in vacuo. The residue was diluted with water (10 mL) and adjusted to the pH=3 with of 1M hydrochloric acid. The resulting solid was collected by filtration to afford crude 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (320 mg, 89.3% yield) as yellow solid used in the next step without further purification: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.67 min, ESI+ found [M+H]=242.9.

Step 3: N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-phenyl-4,5,6,7-tetra hydro-1H-indazole-3-carboxamide

To a solution of 6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (189 mg, 0.78 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (105 mg, 0.78 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (100 mg, 0.52 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (150 mg, 0.78 mmol). The mixture was stirred at 20° C. for 1 h and then concentrated to dryness in vacuo. The residue was purified by RP-HPLC (40-70% acetonitrile in water and 0.05% ammonia hydrate) to afford N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (77 mg, 34% yield as a white solid:

¹H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 7.96 (d, J=8.0, 1H), 7.49 (d, J 7.6 Hz, 1H), 7.34-7.27 (m, 6H), 7.25-7.22 (m, 2H), 4.88-4.83 (m, 1H), 4.52-4.48 (m, 1H), 4.44-4.41 (m, 1H), 3.32 (s, 3H), 2.93-2.69 (m, 4H), 2.58-2.55 (m, 1H), 1.93-1.90 (m, 1H), 1.81-1.78 (m, 1H). LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 2.03 min, ESI+ found [M+H]=417.2.

Example 13 Method K

Step 1: ethyl 2-oxo-2-[2-oxo-5-(trifluoromethyl)cyclohexyl]acetate

To a solution of 4-(trifluoromethyl)cyclohexanone (15.0 g, 90.3 mmol) in ethanol (45 mL) was added a solution of sodium ethoxide (6.8 g, 100.0 mmol) in ethanol (36 mL), following by diethyl oxalate (13.19 g, 90.29 mmol) at 0° C. After addition, the mixture was allowed to warm to 25° C. and stirred for 15 h. The reaction mixture was concentrated to dryness in vacuo to afford crude ethyl 2-oxo-2-[2-oxo-5-(trifluoromethyl)cyclohexyl]acetate (33.0 g, 138% yield) as a yellow solid use in the next step without any further purification:

LCMS (5 to 95% acetonitrile in water+0.04% formic acid over 1.5 mins) retention time 0.861 min, ESI+ found [M+H]=266.9.

Step 2: (R)-ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate and (S)-ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

To a solution of ethyl 2-oxo-2-[2-oxo-5-(trifluoromethyl)cyclohexyl]acetate (33.0 g, 90.3 mmol) in glacial acetic acid (33 mL) was added hydrazine hydrate (6.2 g, 124.0 mmol) at 0° C. The mixture was stirred for 1 h at 25° C., and then adjusted to pH=8 with aqueous sodium bicarbonate. The resulting mixture was extracted with methanol and dichloromethane (3×300 mL, methanol/dichloromethane=5:95). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford racemic ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (5.0 g, 21% yield) as a white solid. In a 500 mg batch, the enantiomers were separated by SFC to afford arbitrarily assigned enantiomers:

Peak 1 (Retention time: 3.36 min):

-   (R)-ethyl     5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate     (180 mg, 36% yield); Peak 2 (Retention time 3.66 min): -   (S)-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate     (132 mg, 26% yield)     SFC condition: Column: Lux Cellulose-2 150×4.6 mm I.D., 3 μm Mobile     phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in     5.5 min and hold 40% for 3 min, then 5% of B for 2.5 min Flow rate:     2.5 mL/min Column temperature: 40° C.

Example 14 Method L

(5R)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide and (5R)-2-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide Step 3: (R)-ethyl 1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate and (R)-ethyl 2-methyl-5-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-2H-indazole-3-carboxylate

To a solution of arbitrarily assigned ethyl (R)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (180 mg, 0.69 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (104 mg, 0.76 mmol). After stirred for 30 min, methyl iodide (86 mg, 0.60 mmol) was added and stirring was continued for 15 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue which was purified by prep-TLC (30% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (Rf=0.2, 72 mg, 37% yield) and (R)-ethyl 2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate (Rf=0.5, 53 mg, 28% yield): ¹H NMR (400 MHz, CDCl₃) δ 4.40-4.35 (m, 2H), 3.80 (s, 3H), 3.22-3.15 (m, 1H), 2.81-2.50 (m, 3H), 2.38-2.40 (m, 1H), 2.31-2.19 (m, 1H), 1.82-1.67 (m, 1H), 1.38 (t, J=7.2 Hz, 3H). LCMS R_(T)=0.835 min, m/z=276.9 [M+H]+; ¹H NMR (400 MHz, CDCl₃) δ 4.37-4.32 (m, 2H), 4.10 (s, 3H), 3.15-3.09 (m, 1H), 2.88-2.83 (m, 1H), 2.72-2.63 (m, 2H), 2.49-2.30 (m, 1H), 2.27-2.13 (m, 1H), 1.76-1.61 (m, 1H), 1.37 (t, J=7.2 Hz, 3H). LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.835 min, ESI+ found [M+H]=276.9 and retention time 0.895 min, ESI+ found [M+H]=276.9.

Step 4: (R)-1-methyl-5-(trifluoromethyl)-4, 5, 6, 7-tetrahydroindazole-3-carboxylic acid

To a solution of arbitrarily assigned ethyl (R)-1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylate (72 mg, 0.26 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (73 mg, 1.3 mmol). The mixture was stirred at 25° C. for 15 h and concentrated to dryness in vacuo. The residue was dissolved in water (5 mL) and adjusted the pH=3 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (3×10 mL). The combined organic layer were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to afford (R)-1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (52 mg, 80% yield) as a white solid used without further purification in the next step: LCMS (0 to 60% acetonitrile in water+0.04% formic acid over 2 mins) retention time 1.10 min, ESI+ found [M+H]=249.0.

Step 5: (5R)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a solution of (R)-1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (52 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-1H-benzo[d][1,2,3]triazol-1-ol (62 mg, 0.46 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (88 mg, 0.46 mmol), and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (88 mg, 0.46 mmol). The reaction mixture was stirred at 25° C. for 12 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.225% formic acid) to afford (5R)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide (21 mg, 25% yield) as a white solid: ¹H NMR (400 MHz, Methanol-d4) δ 7.44-7.41 (m, 1H), 7.33-7.22 (m, 3H), 4.97-4.94 (m, 1H), 4.60-4.56 (m, 1H), 4.37-4.31 (m, 1H), 3.77 (s, 3H), 3.42 (s, 3H), 3.12-3.07 (m, 1H), 2.85-2.81 (m, 1H), 2.68-2.45 (m, 3H), 2.26-2.21 (m, 1H), 1.76-1.63 (m, 1H). LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.64 min, ESI+ found [M+H]=423.2.

Step 6: (R)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid

To a solution of ethyl (R)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylate (53 mg, 0.19 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (62 mg, 1.1 mmol). The mixture was stirred at 25° C. for 15 h and concentrated to dryness in vacuo. The residue was dissolved in water (5 mL) and adjusted the pH=3 with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to afford (R)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (53 mg, 99% yield) as a white solid used without further purification in the next step: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.16 min, ESI+ found [M+H]=249.0.

Step 7: (5R)-2-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide

To a solution of (5R)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (53 mg, 0.21 mmol) in N,N-dimethylformamide (4 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (121 mg, 0.64 mmol), 1-1H-benzo[d][1,2,3]triazol-1-ol (86 mg, 0.64 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (122 mg, 0.64 mmol). The reaction mixture was stirred at 25° C. for 12 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.225% formic acid) to afford (5R)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide (33 mg, 37% yield) as white solid: ¹H NMR (400 MHz, CD₃OD) δ7.45-7.41 (m, 1H), 7.35-7.18 (m, 3H), 5.03-4.97 (m, 1H), 4.60-4.55 (m, 1H), 4.43-4.37 (m, 1H), 3.91 (s, 3H), 3.42 (s, 3H), 3.12-3.05 (m, 1H), 2.87-2.30 (m, 4H), 2.26-2.22 (m, 1H), 1.77-1.71 (m, 1H). LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 7 mins) retention time 6.00 min, ESI+ found [M+H]=423.1.

Example 15 Method M

(5S)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide and (5S)-2-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide

Step 1: (S)-ethyl 1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate and (S)-ethyl 2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate

To a solution of ethyl (S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (132 mg, 0.50 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (104 mg, 0.76 mmol). After stirred for 30 min, methyl iodide (86 mg, 0.60 mmol) was added and stirring was continued for 15 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue which was purified by prep-TLC (30% ethyl acetate in petroleum ether) to afford (S)-ethyl 1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (Rf=0.2, 38 mg, 27.5% yield) and (S)-ethyl 2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (Rf=0.5, 86 mg, 62.3% yield) as a white solid: LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.83 min, ESI+ found [M+H]=276.9 and R_(T)=0.89 min, m/z=276.9 [M+H]⁺.

Step 2: (S)-1-methyl-5-(trifluoromethyl)-4, 5, 6, 7-tetrahydroindazole-3-carboxylic acid

To a solution of (S)-ethyl 1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (38 mg, 0.14 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (38 mg, 0.69 mmol). The mixture was stirred at 25° C. for 15 h and concentrated to dryness in vacuo. The residue was dissolved in water (5 mL) and adjusted the pH=3 with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to dryness in vacuo to afford the product (R)-1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (38 mg, 100% yield) as a white solid: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.12 min, ESI+ found [M+H]=249.0.

Step 3: (5S)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide

To a solution of (S)-1-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (38 mg, 0.14 mmol) in N,N-dimethylformamide (4 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (88 mg, 0.46 mmol), 1-1H-benzo[d][1,2,3]triazol-1-ol (62 mg, 0.46 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (88 mg, 0.46 mmol). The reaction mixture was stirred at 25° C. for 12 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.225% formic acid) to afford (5S)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide (31 mg, 52% yield) as a white solid: ¹H NMR (400 MHz, Methanol-d4) δ 7.46-7.40 (m, 1H), 7.36-7.20 (m, 3H), 4.99-4.94 (m, 1H), 4.60-4.56 (m, 1H), 4.38-4.33 (m, 1H), 3.79 (s, 3H), 3.41 (s, 3H), 3.11-3.06 (m, 1H), 2.85-2.81 (m, 1H), 2.67-2.46 (m, 3H), 2.25-2.21 (m, 1H), 1.75-1.67 (m, 1H). LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 7 mins) retention time 6.20 min, ESI+ found [M+H]=423.2.

Step 4: (S)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid

To a solution of (S)-ethyl 2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (86 mg, 0.31 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (91 mg, 1.60 mmol). The mixture was stirred at 25° C. for 15 h and concentrated to dryness in vacuo. The residue was dissolved in water (5 mL) and adjusted the pH=3 with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to dryness in vacuo to afford (R)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (74 mg, 92% yield) as a white solid. LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.17 min, ESI+ found [M+H]=249.0.

Step 5: (5S)-2-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide

To a solution of (S)-2-methyl-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxylic acid (74 mg, 0.30 mmol) in N,N-dimethylformamide (4 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (121 mg, 0.64 mmol), 1-1H-benzo[d][1,2,3]triazol-1-ol (86 mg, 0.64 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (122 mg, 0.64 mmol). The reaction mixture was stirred at 25° C. for 12 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.225% formic acid) to afford (5S)-2-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-3-carboxamide (33 mg, 26% yield) as a white solid: ¹H NMR (400 MHz, Methanol-d4) δ 7.45-7.41 (m, 1H), 7.36-7.17 (m, 3H), 4.98-4.94 (m, 1H), 4.60-4.55 (m, 1H), 4.44-4.37 (m, 1H), 3.90 (s, 3H), 3.42 (s, 3H), 3.09-3.04 (m, 1H), 2.83-2.60 (m, 4H), 2.28-2.19 (m, 1H), 1.75-1.65 (m, 1H). LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 7 mins) retention time 6.00 min, ESI+ found [M+H]=423.2.

Example 16 Method N

(S)-1-(3,4-difluorobenzyl)-N-(5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-b][1,4]oxazepin-6-yl)-1H-pyrazole-3-carboxamide

Step 1: 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (30.0 g, 265 mmol) in tetrahydrofuran (400 mL) was added sodium hydride (60%, 15.9 g, 398 mmol) at 0° C. The reaction mixture was stirred for 30 min, and (2-(chloromethoxy)ethyl)trimethylsilane (66.3 g, 398 mmol) was added at 0° C. After addition, the mixture was stirred at 25° C. for 2 h and then quenched by addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (60.0 g, 93% yield) used in the next step without further purification.

Step 2: 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (20.0 g, 82.2 mmol) in tetrahydrofuran (300 mL) was added with lithium bis(trimethylsilyl)azanide (1M in tetrahydrofuran, 89.0 mL, 89.0 mmol) at −78° C. The mixture was stirred for 30 min, and hexachloroethane (21.3 g, 90.1 mmol) was added dropwise. After addition, the mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (15.0 g, 66% yield) as colorless oil: ¹H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 5.56 (s, 2H), 3.61 (t, J=8.2 Hz, 2H), 0.86 (t, J=8.2 Hz, 2H), 0.05 (s, 9H).

Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-((4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)oxy)propanoic acid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (1.77 g, 8.64 mmol) in N, N-dimethylformamide (50 mL) was added sodium hydride (60%, 691 mg, 17.28 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, and then 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.40 g, 8.64 mmol) was added. The resulting mixture was stirred at 20° C. for 3 h and quenched by addition of 1M hydrochloric acid (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford (S)-2-((tert-butoxycarbonyl)amino)-3-((4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)oxy)propanoic acid (1.00 g, 26% yield) as yellow oil. LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.99 min, ESI+ found [M+H]=469.1.

Step 4: (S)-3-((4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-((4-nitro-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazol-5-yl)oxy)propanoic acid (600 mg, 1.34 mmol) in methanol (50 mL) was added 10% palladium on carbon (212 mg, 2.00 mmol). The resulting mixture was hydrogenated (50 psi) at 20° C. for 2 h and then filtered through Celite. The filtrate was concentrated to dryness in vacuo to afford crude (S)-3-((4-amino-1-((2-(trimethyl silyl)ethoxy)methyl)-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (500 mg, 89% yield) as yellow oil: LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.831 min, ESI+ found [M+H]=417.2.

Step 5: (S)-tert-butyl (5-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate

To a solution of (S)-3-((4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (500 mg, 1.20 mmol) in N,N-dimethylformamide (10 mL) was added N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (275 mg, 1.44 mmol). The reaction mixture was stirred at 20° C. for 2 h and then concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford (S)-tert-butyl (5-oxo-1-((2-(trimethyl silyl)ethoxy)methyl)-4, 5,6,7-tetrahydro-1H-pyrazol o[3,4-b][1,4]oxazepin-6-yl)carbamate (300 mg, 63% yield) as yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, 1H), 7.22 (s, 1H), 5.79 (s, 1H), 5.35 (d, J=11.2 Hz, 1H), 5.22 (d, J=11.2 Hz, 1H), 4.63 (d, J=11.2 Hz, 1H), 4.53 (s, 1H), 4.24-4.20 (m, 1H), 3.62 (t, J=8.2 Hz, 2H), 1.48 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), 0.01 (s, 9H).

Step 6: (S)-6-amino-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one 2,2,2-trifluoroacetate

To a solution of (S)-tert-butyl (5-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (100 mg, 0.25 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (565 mg, 5.00 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated to dryness in vacuo to afford (S)-6-amino-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one 2,2,2-trifluoroacetate (70 mg, 99% yield) as a yellow solid used without further purification in the next step.

Step 7: ethyl 1-(3,4-difluorobenzyl)-1H-pyrazole-3-carboxylate

A mixture of ethyl 1H-pyrazole-3-carboxylate (1.4 g, 9.66 mmol), 4-(bromomethyl)-1,2-difluorobenzene (1.0 g, 4.83 mmol) and potassium hydroxide (0.27 g, 4.83 mmol) in tetrahydrofuran (100 mL) was stirred at 70° C. for 12 h. After cooling to RT, the mixture was filtered and the filtrate was concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford ethyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (1.2 g, 93% yield) as white solid: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.25 min, ESI+ found [M+H]=266.9.

Step 8: 1-(3,4-difluorobenzyl)-1H-pyrazole-3-carboxylic acid

A mixture of ethyl methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (1.2 g, 4.51 mmol) in ethanol (40 mL) and water (5 mL) was potassium hydroxide (2.5 g, 45.07 mmol) was stirred at 25° C. for 13 h and concentrated to dryness in vacuo. The residue was dissolved with water (5 mL) and adjusted the pH=3 by addition of 1M hydrochloric acid. The resulting solid was collected by filtration and dried under reduced pressure to afford 1-(3,4-difluorobenzyl)-1H-pyrazole-3-carboxylic acid (0.73 g, 68% yield) as a white solid: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.07 min, ESI+ found [M+H]=238.9.

Step 9: (S)-1-(3,4-difluorobenzyl)-N-(5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-b][1,4]oxazepin-6-yl)-1H-pyrazole-3-carboxamide

To a solution of (S)-6-amino-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one 2,2,2-trifluoroacetate (70.0 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3,4-difluorobenzyl)-1H-pyrazole-3-carboxylic acid (71.4 mg, 0.30 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (40.5 mg, 0.30 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (57.3 mg, 0.30 mmol). The reaction mixture was heated to 50° C. for 16 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (18-48% acetonitrile in water and 0.05% ammonia hydroxide) to afford (S)-1-(3,4-difluorobenzyl)-N-(5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-pyrazole-3-carboxamide (5.9 mg, 6.1% yield) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.78 (d, J=2.4 Hz, 1H), 7.36 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.26-7.20 (m, 2H), 7.14-7.10 (m, 1H), 6.80 (d, J=2.0 Hz, 1H), 5.41 (s, 2H), 4.89-4.85 (m, 1H), 4.53-4.50 (m, 1H), 4.33-4.28 (m, 1H). LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.74 min, ESI+ found [M+H]=389.0.

Example 17 Method O

1-[(3,4-difluorophenyl)methyl]-N-[(6S)-5-oxo-1,4,6,7-tetrahydropyrazolo[3,4-b][1,4]oxazepin-6-yl]imidazole-4-carboxamide

Step 1: methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate

A mixture of 4-(bromomethyl)-1,2-difluorobenzene (10.0 g, 48.3 mmol), 1H-imidazole-4-carboxylate (12.2 g, 96.6 mmol) and potassium hydroxide (5.4 g, 96.6 mmol) in tetrahydrofuran (100 mL) was heated at 70° C. for 12 h. After cooled, the mixture was filtered and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (5.0 g, 41% yield) as a white solid: LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.70 min, ESI+ found [M+H]=252.8.

Step 2: 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylic acid

A mixture of methyl 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylate (5.0 g, 19.07 mmol) in ethanol (50 mL) and water (5 mL) was added potassium hydroxide (5.4 g, 95.34 mmol). The mixture was stirred at 25° C. for 13 h and concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and adjusted the pH=3 by addition of 1M hydrochloric acid. The resulting solid was collected by filtration and dried under reduced pressure to afford 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylic acid (4.5 g, 99.1% yield) as a white solid:

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.22 min, ESI+ found [M+H]=238.8.

Step 3: 1-[(3,4-difluorophenyl)methyl]-N-[(6S)-5-oxo-1,4,6,7-tetrahydropyrazolo[3,4-b][1,4]oxazepin-6-yl]imidazole-4-carboxamide

To a solution of (S)-6-amino-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one 2,2,2-trifluoroacetate (70 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3,4-difluorobenzyl)-1H-imidazole-4-carboxylic acid (71 mg, 0.30 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (41 mg, 0.30 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (57 mg, 0.30 mmol). The mixture was heated at 50° C. for 16 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (17-47% acetonitrile in water and 0.05% ammonia hydroxide) to afford (S)-1-(3,4-difluorobenzyl)-N-(5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-imidazole-4-carboxamide (4.9 mg, 5.1% yield) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ7.79 (s, 1H), 7.74 (s, 1H), 7.36 (s, 1H), 7.32-7.24 (m, 2H), 7.14-7.05 (m, 1H), 5.26 (s, 2H), 4.82-4.50 (m, 1H), 4.51-4.48 (m, 1H), 4.31-4.26 (m, 1H). LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.36 min, ESI+ found [M+H]=389.1.

Example 18 Method P

5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,6,7-tetrahydroindazole-3-carboxamide

Step 1: ethyl 2-(5,5-dimethyl-2-oxocyclohexyl)-2-oxoacetate

To a solution of 4,4-dimethylcyclohexanone (2.5 g, 19.8 mmol) in ethanol (30 mL) was added a solution of sodium ethoxide (1.5 g, 21.8 mmol) in ethanol (30 mL), followed by diethyl oxalate (2.9 g, 19.8 mmol) at 0° C. After addition, the mixture was stirred at 25° C. for 15 h and concentrated to dryness in vacuo to afford crude ethyl 2-(5,5-dimethyl-2-oxocyclohexyl)-2-oxoacetate (4.5 g, 100% yield) as a yellow solid used in the next step without further purification.

Step 2: 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

To a solution of ethyl 2-(5,5-dimethyl-2-oxocyclohexyl)-2-oxoacetate (4.47 g, 21.8 mmol) in glacial acetic acid (5 mL) was added hydrazine hydrate (0.18 g, 21.8 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h and then adjusted to pH=8 by addition of aqueous sodium bicarbonate. The resulting mixture was extracted with methanol and dichloromethane (3×300 mL, methanol/dichloromethane=5:95). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford ethyl 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (700 mg). The above material was dissolved in THF (10 mL) and water (2 mL), and added lithium hydroxide monohydrate (500 mg, 11.9 mmol). The mixture was stirred at 25° C. for 12 h and concentrated to dryness in vacuo. The residue was diluted with water (10 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was then adjust to pH=3 by addition of 1M HCl. The solution was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to afford 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (100 mg, 2.5% yield over 2 steps) as a white solid: LCMS (5 to 95% acetonitrile in water+0.04% formic acid over 1.5 mins) retention time 0.66 min, ESI+ found [M+H]=195.1.

Step 3: 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,6,7-tetrahydroindazole-3-carboxamide

To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (100 mg, 0.51 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (76 mg, 0.56 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (108 mg, 0.56 mmol) and N-1-((ethylamine)ethylene)-N₃,N₃-dimethylpropane-1,3-diamine hydrochloride (108 mg, 0.56 mmol). The mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (45-75% acetonitrile in water and 0.05% hydrochloric acid) to afford 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,6,7-tetrahydroindazole-3-carboxamide (30 mg, 15.8% yield) as white solid: ¹H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=8.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.31-7.19 (m, 3H), 4.82-4.77 (m, 1H), 4.51-4.34 (m, 2H), 3.29 (s, 3H), 2.57-2.52 (m, 2H), 2.32 (s, 2H), 1.45 (t, J=6.4 Hz, 2H), 0.88 (s, 6H). LCMS (5 to 95% acetonitrile in water+0.04% formic acid over 1.5 mins) retention time 0.86 min, ESI+ found [M+H]=369.0.

Example 19 Method Q

5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

8-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

Step 1: 7-methyloxepan-4-one and 2-methyloxepan-4-one

To a solution of 2-methyldihydro-2H-pyran-4(3H)-one (3.0 g, 26.68 mmol) in dichloromethane (60 mL) and boron fluoride ethyl ether (8.1 mL, 48% ethyl ether) was added trimethylsilyldiazomethane (14.5 mL, 28.91 mmol, 2 M in hexane) dropwise at −30° C. After addition, the resulting solution was stirred for 1 h at −30° C. and quenched by addition of saturated sodium bicarbonate (30 mL). The resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford a mixture of 7-methyloxepan-4-one and 2-methyloxepan-4-one (1.2 g, 35.1% yield) as a yellow oil used in the next step without further purification.

Step 2: ethyl 5-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate; ethyl 7-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate; ethyl 8-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate and ethyl 6-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate

To a solution of 7-methyloxepan-4-one and 2-methyloxepan-4-one (1.00 g, 7.8 mmol) in dimethyl sulfoxide (30 mL) was added ethyl diazoacetate (1.07 g, 9.4 mmol), pyrrolidine (0.11 g, 1.56 mmol). The mixture was stirred at 20° C. for 16 h and diluted with water (20 mL). The solution was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (3×25 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford:

ethyl 5-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (120 mg, 6.9% yield) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 4.38 (q, J=6.8 Hz, 2H), 4.24-4.20 (m, 1H), 3.63-3.55 (m, 2H), 3.45-3.41 (m, 1H), 3.06-3.05 (m, 1H), 2.97-2.89 (m, 1H), 2.70-2.63 (m, 1H), 1.40 (t, J=7.2 Hz, 3H), 1.33 (d, J=6.4 Hz, 3H); ethyl 7-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (120 mg, 6.9% yield) as yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 4.38 (q, J=7.2 Hz, 2H), 4.26-4.22 (m, 1H), 3.67-3.56 (m, 1H), 3.54-3.49 (m, 1H), 3.37-3.32 (m, 1H), 3.04-2.90 (m, 1H), 2.90-2.83 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.32 (d, J=6.0 Hz, 3H); ethyl 8-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate (250 mg, 14.3% yield) as yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 4.60-4.55 (m, 1H), 4.44-4.35 (m, 2H), 4.33-4.28 (m, 1H), 3.86-3.79 (m, 1H), 3.39-3.34 (m, 1H), 2.80-2.76 (m, 1H), 1.90-1.83 (m, 2H), 1.65 (d, J=6.4 Hz, 3H), 1.39 (t, J=7.2 Hz, 3H) and ethyl 6-methyl-4,5,6, 8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate (250 mg, 14.3% yield) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 4.92 (d, J=14.4 Hz, 1H), 4.52 (d, J=14.4 Hz, 1H), 4.41-4.35 (m, 2H), 3.86-3.82 (m, 1H), 3.43-3.37 (m, 1H), 2.70-2.65 (m, 1H), 2.00-1.92 (m, 1H), 1.64-1.61 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.29 (d, J=6.4 Hz, 3H).

Step 3: 5-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid

To a solution of ethyl 5-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (110 mg, 0.49 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (118 mg, 4.91 mmol). The mixture was stirred at 20° C. for 20 h and then concentrated to dryness in vacuo. The residue was diluted with water (30 mL) and adjusted pH=3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford the crude 5-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid (100 mg, 100% yield) as a white solid: LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.86 min, ESI+ found [M+H]=196.9.

Step 4: 5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

To a solution of 5-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid (50.0 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (41.3 mg, 0.31 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (58.6 mg, 0.31 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (53.9 mg, 0.28 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (50-80% methanol in water and 0.05% ammonia) to afford 5-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide (30.0 mg, 32% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.01-7.99 (m, 1H), 7.49-7.47 (m, 1H), 7.32-7.28 (m, 2H), 7.24-7.21 (m, 1H), 4.82-4.79 (m, 1H), 4.42-4.39 (m, 1H), 4.37-4.35 (m, 1H), 4.07-4.04 (m, 1H), 3.49-3.45 (m, 3H), 3.31 (s, 3H), 2.87-2.80 (m, 2H), 2.49-2.35 (m, 1H), 1.13 (d, J=6.0 Hz, 3H). LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=371.0.

7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

Step 5: 7-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid

To a solution of ethyl 7-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (120 mg, 0.54 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (128 mg, 5.35 mmol). The mixture was stirred at 20° C. for 20 h and then concentrated to dryness in vacuo. The residue was diluted with water (30 mL) and adjusted pH=3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford crude 7-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid (100 mg, 95% yield) as a white solid used without further purification in the next step:

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.85 min, ESI+ found [M+H]=197.0.

Step 6: 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

To a solution of 7-methyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid (50.0 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (41.3 mg, 0.31 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (58.6 mg, 0.31 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (53.9 mg, 0.28 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (50-80% methanol in water and 0.05% ammonia) to afford 7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide (20 mg, 21% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.00-7.97 (m, 1H), 7.49-7.47 (m, 1H), 7.32-7.28 (m, 2H), 7.24-7.23 (m, 1H), 4.84-4.79 (m, 1H), 4.50-4.44 (m, 1H), 4.42-4.39 (m, 1H), 4.05-4.01 (m, 1H), 3.61-3.58 (m, 1H), 3.38-3.36 (m, 1H), 3.31 (s, 3H), 3.30-3.26 (m, 1H), 2.87-2.83 (m, 1H), 2.71-2.65 (m, 1H), 2.61-2.50 (m, 1H), 1.19 (d, J=6.4 Hz, 3H).

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=371.0.

8-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

Step 7: 8-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid

To a solution of ethyl 8-methyl-4,5,6, 8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate (250 mg, 1.11 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (267 mg, 11.15 mmol). The mixture was stirred at 20° C. for 20 h and concentrated to dryness in vacuo. The residue was diluted with water (30 mL) and adjusted pH=3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford crude 8-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid (200 mg, 91% yield) as a white solid: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2.0 mins) retention time 1.26 min, ESI+ found [M+H]=197.2.

Step 8: 8-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

To a solution of 8-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid (70.0 mg, 0.35 mol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (57.9 mg, 0.43 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (82.1 mg, 0.43 mmol), and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (75.4 mg, 0.39 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (21-51% acetonitrile in water and 0.05% ammonia) to afford 8-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide (65 mg, 49% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.00 (br. s, 1H), 7.50-7.47 (m, 1H), 7.33-7.28 (m, 2H), 7.26-7.24 (m, 1H), 4.84-4.81 (m, 1H), 4.63-4.60 (m, 1H), 4.48-4.39 (m, 2H), 4.09-4.07 (m, 1H), 3.73-3.70 (m, 1H), 3.32 (s, 3H), 3.20-3.17 (m, 1H), 2.70-2.65 (m, 1H), 1.78-1.70 (m, 1H), 1.62-1.59 (m, 1H), 1.48 (d, J=6.8 Hz, 3H). LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=371.0.

6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

Step 9: 6-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid

To a solution of ethyl 6-methyl-4,5,6, 8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate (250 mg, 1.1 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (267 mg, 11.15 mmol). The mixture was stirred at 20° C. for 20 h and concentrated to dryness in vacuo. The residue was diluted with water (30 mL) and adjusted pH=3 by addition of 1 M hydrochloric acid. The resulting solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford the crude 6-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid (200 mg, 91% yield) as a white solid: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2.0 mins) retention time 1.27 min, ESI+ found [M+H]=197.2.

Step 10: 6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

To a solution of 6-methyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid (70.0 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (57.9 mg, 0.43 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (82.1 mg, 0.43 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (75.4 mg, 0.39 mmol), The reaction mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (23-53% acetonitrile in water and 0.05% ammonia) to afford 6-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4, 5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide (62 mg, 47% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 8.05-8.03 (m, 1H), 7.50-7.47 (m, 1H), 7.33-7.23 (m, 3H), 4.84-4.80 (m, 1H), 4.70 (d, J=14.8 Hz, 1H), 4.49-4.40 (m, 3H), 3.78-3.74 (m, 1H), 3.31 (s, 3H), 3.30-3.24 (m, 1H), 2.49-2.47 (m, 1H), 1.83-1.78 (m, 1H), 1.41-1.32 (m, 1H), 1.15 (d, J=6.0 Hz, 3H). LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=371.1.

Example 20 Method R

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

Step 1: 1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 1,4-dioxaspiro[4.5]decan-8-one (10.0 g, 64.0 mmol) in methanol (150 mL) was added sodium borohydride (2.5 g, 66.1 mmol) at 0° C. The mixture was warmed to 20° C. for 3 h and then poured into water (150 mL). The resulting mixture was extracted with dichloromethane (3×200 mL). The combined organic phases were filtered through a cotton plug, and the filtrate was concentrated to dryness in vacuo to afford 1,4-dioxaspiro[4.5]decan-8-ol (7.0 g, 69% yield) used without further purification in the next step: ¹H NMR (400 MHz, CDCl₃) δ 3.95-3.91 (m, 4H), 3.80-3.77 (m, 1H), 1.87-1.80 (m, 4H), 1.69-1.56 (m, 5H).

Step 2: 1,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate

A solution of 1,4-dioxaspiro[4.5]decan-8-ol (7.0 g, 44.25 mmol) in pyridine (70 mL) was treated with 4-methylbenzenesulfonyl chloride (10.1 g, 53.1 mmol). The reaction mixture was stirred at 20° C. for 16 h and then quenched by addition of brine (50 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organics were washed with 0.5 M HCl (100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over sodium sulfate and concentrated to dryness in vacuo to afford 1,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (10.0 g, 72.3% yield) as a clear liquid used without further purification in the next step: ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 4.63-4.60 (m, 1H), 3.93-3.86 (m, 4H), 2.42 (s, 3H), 1.84-1.76 (m, 6H), 1.54-1.50 (m, 2H).

Step 3: 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole

To a mixture of sodium hydride (60%, 0.97 g, 24.24 mmol) in N,N-dimethylformamide (5 mL) was slowly added 1H-pyrazole (1.65 g, 24.24 mmol) at 0° C. The reaction mixture stirred for 30 min, and 1,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (6.26 g, 20.03 mmol) was added. After addition, the reaction mixture was stirred at 0° C. for 10 min and at 60° C. for 5 h. The reaction mixture was cooled and quenched by addition of water (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazole (2.0 g, 48% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=2.0 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 6.20 (t, J=2.0 Hz, 1H), 4.29-4.21 (m, 1H), 3.87-3.90 (m, 4H), 1.98-1.93 (m, 4H), 1.75-1.65 (m, 4H).

Step 4: 4-(1H-pyrazol-1-yl)cyclohexanone

A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole (2.0 g, 9.60 mmol) and 36% HCl (4.9 g, 48.02 mmol) in THF (20 ml) was stirred at ambient temperature for 20 h. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford crude 4-(1H-pyrazol-1-yl)cyclohexanone (1.5 g, 95% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J=2.4 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 6.26 (t, J=1.8 Hz, 1H), 4.74-4.67 (m, 1H), 2.59-2.52 (m, 2H), 2.33-2.17 (m, 6H).

Step 5: ethyl 2-oxo-2-(2-oxo-5-(1H-pyrazol-1-yl)cyclohexyl)acetate

To a solution of 4-pyrazol-1-ylcyclohexanone (1.2 g, 7.31 mmol) in ethanol (15 mL) was added a solution of sodium ethanoxide in ethanol (10 mL) at 0° C. The reaction mixture was stirred for further 10 min and diethyl oxalate (1.1 g, 7.31 mmol) was added. The resulting mixture was stirred at RT for 20 h and concentrated to dryness in vacuo to afford ethyl 2-oxo-2-(2-oxo-5-pyrazol-1-yl-cyclohexyl)acetate (2.0 g, over 100% yield) as a yellow solid use in the next step without further purification.

Step 6: ethyl 5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

To a solution of ethyl 2-oxo-2-(2-oxo-5-pyrazol-1-yl-cyclohexyl)acetate (1.90 g, 7.19 mmol) in acetic acid (10 mL) was added 50% hydrazine in water (0.52 g, 8.04 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h and then quenched by addition of saturated aqueous sodium bicarbonate. The mixture was extracted with methanol/dichloromethane (3×50 mL, 1:10). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford ethyl 5-pyrazol-1-yl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (1.0 g, 53% yield) as a yellow solid: LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.61 min, ESI+ found [M+H]=260.9.

Step 7: 5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

To a solution of ethyl 5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (200 mg, 0.77 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (92 mg, 3.83 mmol). The mixture was stirred at RT for 20 h and concentrated to dryness in vacuo. The residue was diluted with water (10 mL) and then adjusted to pH=3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (100 mg, 56% yield) as a white solid: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 3 mins) retention time 1.36 min, ESI+ found [M+H]=233.2.

Step 8: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a solution of 1H-benzo[d][1,2,3]triazol-1-ol (49 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL) was added N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (69 mg, 0.36 mmol), 6,6-dimethyl-1,4,5,8-tetrahydrooxepino[3,4-c]pyrazole-3-carboxylic acid (63 mg, 0.30 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (64 mg, 0.33 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (28-58% acetonitrile in water and 0.05% ammonia) to afford N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1H-pyrazol-1-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (60 mg, 49% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 13.00 (br. s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.50-7.42 (m, 2H), 7.35-7.19 (m, 3H), 6.26-6.18 (m, 1H), 4.87-4.77 (m, 1H), 4.62-4.46 (m, 2H), 4.44-4.36 (m, 1H), 3.31 (s, 3H), 3.20-3.10 (m, 1H), 2.98-2.65 (m, 3H), 2.25-2.09 (m, 2H). LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=407.1.

Example 21 Method S

1-ethyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1, 3-dihydrofuro[3,4-c]pyridine-6-carboxamide and 1-ethyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-4-carboxamide

Step 1: 4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one

n-BuLi (2.5 M in hexane, 16 mL, 40 mmol) was added dropwise to a solution of diisopropylamine (4.7 g, 46.5 mmol) at −78° C. The mixture was stirred at −78° C. for 40 min and a solution of 2,6-dichloronicotinic acid (3 g, 15.6 mmol) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at −78° C. and the resultant mixture was stirred at −78° C. for 3 h. Butanone (10 g, 139 mmol) was added dropwise to the reaction mixture at −78° C. and the reaction mixture was warmed slowly to RT and stirred for 16 h. The reaction mixture was cooled to 0° C., quenched with sat. ammonium chloride to pH 7 and acidified with 3 N HCl to pH 4. The mixture was extracted with ethyl acetate (30 mL×4). The combined organic layers were combined, dried over sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 8:1 to 6:1 to 4:1 ethyl acetate: petroleum ether) to afford 4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one as a brown solid (1.3 g, Yield 34%). LCMS: m/z=246.0/248.1 [M+1]. Column: MERCK RP18 (50-3). Mobile phase: H₂O(0.01% TFA) (A)/ACN(0.01% TFA)(B) Elution program: Gradient from 10 to 95% of B in 1.8 min at 2.0 ml/min. Temperature: 45° C. 3 min gradient.

Step 2: 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol

To a stirred suspension of 4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (1.3 g, 5.28 mmol) in toluene (30 mL) was added diisobutyl aluminium hydride (1 M in toluene, 12 mL, 12 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 h and quenched with saturated ammonium chloride (50 ml) dropwise at −78° C. The mixture was warmed slowly to RT and stirred for 30 min. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (30 mL×3). The combined organic layers were combined, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 4:1 to 2:1 ethyl acetate:petroleum ether) to afford 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (1 g, Yield 76%) as a colorless oil: LCMS: m/z=248.0/250.1 [M+1]. Column: MERCK RP18 (50-3). Mobile phase: H₂O(0.01% TFA) (A)/ACN(0.01% TFA)(B) Elution program: Gradient from 10 to 95% of B in 1.8 min at 2.0 ml/min. Temperature: 45° C. 3 min gradient.

Step 3: 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine

To a stirred solution of 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (1 g, 4.06 mmol) in dichloromethane (10 ml) was added dropwise trifluoroacetic acid (1.5 mL, 20.1 mmol) at 0° C. and the mixture was stirred at 0° C. for 30 min. Triethylsilane (2 mL, 12.55 mmol) was added dropwise to the reaction mixture at 0° C. and the reaction mixture was warmed slowly to RT and stirred at RT for 2 h. The reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (50 mL) and adjusted to pH=7 by addition of saturated sodium bicarbonate. The ethyl acetate layer was separated, dried over sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 8:1 ethyl acetate:petroleum ether) to afford 4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine (0.83 g, Yield 88%) was got as a white solid. LCMS: m/z=232.1/234.1 [M+1]. Column: MERCK RP18 (50-3). Mobile phase: H₂O(0.01% TFA) (A)/ACN(0.01% TFA)(B) Elution program: Gradient from 10 to 95% of B in 1.8 min at 2.0 ml/min. Temperature: 45° C. 3 min gradient.

Step 1: methyl 4-chloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate and methyl 6-chloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylate

To a solution of 4,6-dichloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine (0.50 g, 2.15 mmol) in methanol (10 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.16 g, 0.22 mmol) and triethylamine (2.18 g, 21.54 mmol). The reaction mixture was stirred at 80° C. for 15 h under the carbon monoxide (25 psi). After cooling to RT the reaction mixture was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford methyl 4-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate and methyl 6-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylate (140 mg (3:1 mixture), 0.55 mmol, 25.5% yield mixture) as a light yellow oil used as is in the next step without further purification.

Step 2: methyl 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate and methyl 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylate

To a solution of methyl 4-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate and methyl 6-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylate (140 mg, 0.55 mmol) in methanol (10 mL) was added 10% palladium (437 mg, 0.41 mmol) on carbon. The reaction mixture was hydrogenated (15 psi) at 20° C. for 1 h and then filtered through Celite. The filtrate was concentrated to dryness in vacuo to afford methyl 1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylate and methyl 1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate (100 mg, 82.6% yield) as a yellow oil: LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.65 min, ESI+ found [M+H]=222.

Step 3: 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid and 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylic acid

To a solution of methyl 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate and methyl 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylate (100 mg, 0.46 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (202 mg, 4.81 mmol). The reaction mixture was stirred at 15° C. for 15 h and concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and adjusted to pH=3 by addition of 1 M hydrochloric acid. The mixture was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid and 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylic acid (50 mg, 50.5% yield) as a yellow oil used in the next step without further purification.

Step 4: 1-ethyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1, 3-dihydrofuro[3,4-c]pyridine-6-carboxamide and 1-ethyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1, 3-dihydrofuro[3,4-c]pyridine-4-carboxamide

To a solution of 1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid and 1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylic acid (3:1 mixture, 41 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) was added N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (59 mg, 0.31 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (35 mg, 0.26 mmol). The reaction mixture was stirred at 15° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (40-70% acetonitrile in water and 0.05% ammonia hydroxide) to afford:

1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-6-carboxamide (15 mg, 20.7% yield) as white solid and 1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-4-carboxamide (7 mg, 9.6% yield) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.86 (s, 1H), 7.45-7.43 (m, 1H), 7.39-7.29 (m, 2H), 7.26-7.25 (m, 1H), 5.16 (d, J=3.6 Hz, 2H), 5.05-5.00 (m, 1H), 4.67-4.62 (m, 1H), 4.41 (t, J=9.6, 1H), 3.43 (s, 3H), 1.88-1.82 (m, 2H), 1.46 (s, 3H), 0.77 (t, J=7.2, 3H); LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) R_(T)=0.87 min, m/z=382.0 [M+H]⁺ and ¹H NMR (400 MHz, CD₃OD) δ 8.60 (d, J=5.6 Hz, 1H), 7.45-7.42 (m, 2H), 7.34-7.24 (m, 3H), 5.33-5.28 (m, 2H), 5.02-4.97 (m, 1H), 5.16 (d, J=3.6 Hz, 2H), 5.05-5.00 (m, 1H), 4.63 (t, J=10.0 Hz, 1H), 4.41 (t, J=9.6 Hz, 1H), 3.43 (s, 3H), 1.87-1.81 (m, 2H), 1.45 (s, 3H), 0.75 (t, J=7.6 Hz, 3H); LCMS (10 to 80% acetonitrile in water+0.03% trifluoroacetic acid over 2.0 mins) R_(T)=1.17 min, m/z=382.3 [M+H]⁺.

Example 22 Method T

(S)-1,1-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

6-chloro-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-one and similar starting materials for Method T are commercially purchased or prepared according to exemplary procedures shown in: WO 2005080342 A1; WO 2005074939 A1; and WO 2004029026 A1.

Step 1: 6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol

A stirred solution of 6-chloro-1,-dimethylfuro[3,4-c]pyridin-3(1H)-one (18.5 g, 0.09362 mol) in dry toluene (300 mL) at RT under nitrogen was cooled to −70° C. was added dropwise diisobutylaluminum hydride (197.24 mL, 0.18724 mol, 1M in Toluene) and the reaction mixture and allowed to stir at −70° C. for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and filtered. The filtrate was extracted with ethyl acetate (2×200 mL) and the combined organic layer was washed the water, brine, dried over anhydrous sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate:petroleum ether) to afford 6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (17.5 g, 94%): ¹H NMR (400 MHz, DMSO-d6) δ 8.4 (s, 1H), 7.65 (s, 1H), 7.2-6.40 br., s, 1H), 6.35 (s, 1H), 1.35 (s, 3H), 1.23 (s, 3H).

Step 2: 6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine

6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (17.5 g, 0.0877 mol) was dissolved in dry dichloromethane and cooled to 0° C. under nitrogen. To the stirred solution was added dropwise trifluoroacetic acid (32.66 ml 0.438 mol.) and stirred for 30 min at 0° C. Triethyl silane (42.47 ml, 0.263 mol) was added to the reaction mixture at 0° C. at and stirred at RT for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2×200 mL). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate:petroleum ether) to afford 6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine (15.2 g, 94%): LCMS R_(T)=1.55 min, m/z=184.04 [M+H]⁺. Column:Acquity UPLC BEH C-18 (2.1×50 mm) 1.7u; MP:A: 0.05% FA in Water, B: 0.05% FA in Acetonitrile; T/% B 0/10, 0.5/10, 1/35, 1.5/45, 2.3/90, 3.2/90, 3.6/10, 4/10; Flow: 0.55 mL; Diluent ACN+WATER (70:30); Column temp:35° C.

Step 3: 1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-6-amine

To a stirred solution of 6-chloro-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine (15.0 g, 0.082 mol) in dry tetrahydrofuran was added benzophenone imine (15.39 g, 0.085 mol.) and cesium carbonate (39.92 g, 0.12254) under a nitrogen atmosphere. The resulting solution was degassed with nitrogen for 10 min and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.88 g, 0.003 mol) and palladium(II) acetate (0.440 g, 0.002 mol.) were added under a nitrogen atmosphere. Reaction mixture was heated at reflux for 11 h. Reaction was cooled to RT, filtered through Celite and washed with ethyl acetate. The filtrate was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated to dryness in vacuo. The residue was dissolved in tetrahydrofuran, cooled to 0° C. and 2N HCl (30 mL) was added to reaction mixture and stirred at to RT for 3 h. The reaction mixture was poured into water, extracted with ether and the aqueous layer was adjusted to pH=8 by addition of sodium bicarbonate. The mixture was extracted with ethyl acetate (2×200 mL), dried over anhydrous sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-6-amine (3 g, 29%) as a white solid: LCMS R_(T)=1.09 min, m/z=165.11 [M+H]⁺.

Step 4: 6-bromo-1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine

To a solution of 1,1-dimethyl-3H-furo[3,4-c]pyridin-6-amine (200 mg, 1.22 mmol) in hydrobromic acid (0.06 mL, 1.22 mmol) was added sodium nitrite (210 mg, 3.05 mmol) in water (0.2 mL) and bromine (0.12 mL, 2.44 mmol) at −25° C. The reaction was stirred at −25° C. for 1 h and warmed to 15° C. over 30 min. The solution was diluted with 5 M sodium hydroxide (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 6-bromo-1,1-dimethyl-3H-furo[3,4-c]pyridine (150 mg, 54% yield) as a colorless oil use in the next step without further purification.

Step 5: methyl 1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate

To a solution of 6-bromo-1,1-dimethyl-3H-furo[3,4-c]pyridine (150 mg, 0.66 mmol) in methanol (10 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (48 mg, 0.07 mmol) and triethylamine (665 mg, 6.58 mmol). The reaction mixture was stirred at 80° C. for 15 h under the carbon monoxide (25 psi). The reaction mixture was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl 1,1-dimethyl-3H-furo[3,4-c]pyridine-6-carboxylate (100 mg, 73.4% yield) as a pale yellow oil: LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.97 min, ESI+ found [M+H]=208.2.

Step 6: 1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid

To a solution of methyl 1,1-dimethyl-3H-furo[3,4-c]pyridine-6-carboxylate (100 mg, 0.48 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (202 mg, 4.83 mmol). The reaction mixture was stirred at 15° C. for 15 h and then concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and then adjusted to pH=3 by addition of 1 M hydrochloric acid. The mixture was extracted with dichloromethane (3×15 mL). The combined layers were dried over sodium sulfate and concentrated to afford crude 1,1-dimethyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (50 mg, 53.9% yield) as a yellow oil used in the next step without further purification.

Step 7: S)-1,1-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was added 1,1-dimethyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (56 mg, 0.29 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (60 mg, 0.31 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (42 mg, 0.31 mmol). The reaction mixture was stirred at 15° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (35-65% acetonitrile in water and 0.05% ammonia hydroxide) to afford 1,1-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-6-carboxamide (18 mg, 18.8% yield) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.91 (s, 1H), 7.44-7.43 (m, 1H), 7.34-7.31 (m, 2H), 7.26-7.25 (m, 1H), 5.15 (s, 2H), 5.05-5.00 (m, 1H), 4.65-4.62 (m 1H), 4.43-3.98 (m, 1H), 3.43 (s, 3H), 1.49 (s, 6H).

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.84 min, ESI+ found [M+H]=368.0.

Example 23 Method U

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamide

Step 1: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamide

To a solution of 5,6,7,8-tetrahydroisoquinoline-3-carboxylic acid (80 mg, 0.45 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (96 mg, 0.50 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (104 mg, 0.54 mmol) and 1-hydroxybenzotriazole (73 mg, 0.54 mmol). The reaction mixture was stirred at RT for 12 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (0-40% acetonitrile in water and 0.1% ammonia hydroxide) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroisoquinoline-3-carboxamide (26 mg, 16.5% yield) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.71 (s, 1H), 7.43 (d, J=6.0 Hz, 1H), 7.37-7.19 (m, 3H), 5.02-4.97 (m, 1H), 4.64-4.60 (m, 1H), 4.37 (t, J=10.8 Hz, 1H), 3.42 (s, 3H), 2.83-2.81 (m, 4H), 1.87-1.82 (m, 4H). LCMS (10-80% acetonitrile in water+0.03% trifluoroacetic over 2 mins) retention time 1.15 min, ESI+ found [M+H]=352.2.

Example 24 Method V

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

Step 1: ethyl 2-oxo-2-(2-oxo-5-phenylcyclohexyl)acetate

To a solution of 4,4-dimethylcyclohexanone (2.50 g, 19.8 mmol) in ethanol (30 mL) was added a solution of sodium ethoxide (1.48 g, 21.8 mmol) in ethanol (30 mL), followed by diethyl oxalate (2.9 g, 19.8 mmol) at 0° C. After addition, the mixture was stirred at 25° C. for 15 h and concentrated to dryness in vacuo to afford crude ethyl 2-oxo-2-(2-oxo-5-phenylcyclohexyl)acetate (5.4 g, 99.4% yield) as a yellow solid used in the next step without further purification.

Step 2: ethyl 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

To a solution of ethyl 2-oxo-2-(2-oxo-5-phenylcyclohexyl)acetate (5.4 g, 19.7 mmol) in glacial acetic acid (5 mL) was added hydrazine hydrate (1.09 g, 21.8 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h and then adjusted to pH=8 by addition of aqueous sodium bicarbonate. The resulting solid was collected by filtration and dried to afford crude ethyl 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (1.5 g, 28% yield) use in the next step without further purification.

Step 3: 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

To a solution of ethyl 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (405 mg, 1.5 mmol) in tetrahydrofuran (8 mL) and water (4 mL) was added lithium hydroxide hydrate (621 mg, 14.8 mmol). The mixture was stirred at 25° C. for 25 h and concentrated to dryness in vacuo. The residue was diluted with water (5 mL) and adjusted the pH=3 by addition of 1 N hydrochloric acid. The resulting solid was collected by filtration and dried to afford crude 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (330 mg, 90.9% yield) as white solid: LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.77 min, ESI+ found [M+H]=242.9.

Step 4: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a stirred solution of 5-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (94 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (53 mg, 0.39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (75 mg, 0.39 mmol). The mixture was stirred at 20° C. for 1 h and then concentrated to dryness in vacuo. The residue was purified by RP-HPLC (42-72% actonitrile in water and 0.05% ammonia hydroxide) to afford N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-4, 5,6,7-tetra hydro-1H-indazole-3-carboxamide (73 mg, 67.6% yield) as white solid: ¹H NMR (400 MHz, DMSO-d6) δ12.95 (s, 1H), 7.97-7.95 (m, 1H), 7.48-7.45 (m, 1H), 7.33-7.25 (m, 6H), 7.23-7.17 (m, 2H), 4.85-4.78 (m, 1H), 4.54-4.47 (m, 1H), 4.42-4.37 (m, 1H), 3.31 (s, 3H), 2.98-2.92 (m, 1H), 2.88-2.83 (m, 1H), 2.72-2.67 (m, 2H), 2.56-2.53 (m, 1H), 1.98-1.89 (m, 2H). LCMS (10 to 80% acetonitrile in water+0.03% trifluoroacetic acid over 3 mins) retention time 1.19 min, ESI+ found [M+H]=417.3.

Example 25 Method W

5-methyl-N—((S)-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

To a solution of (S)-6-amino-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one 2,2,2-trifluoroacetate (70 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (41 mg, 0.30 mmol), 5-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (55 mg, 0.30 mmol), and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (57 mg, 0.30 mmol). The reaction mixture was heated at 50° C. for 16 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (0 to 27% acetonitrile in water and 0.05% hydrochloric acid) to afford 5-methyl-N—((S)-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (3.3 mg, 4%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.52 (s, 1H), 4.91-4.74 (m, 3H), 4.58-4.54 (m, 1H), 4.39-4.35 (m, 1H), 3.75-3.71 (m, 1H), 3.00-2.88 (m, 1H), 2.55-2.51 (m, 1H), 1.36 (d, J=3.2 Hz, 3H). LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.35 min, ESI+ found [M+H]=333.0.

Example 26 Method X (S)-5,5-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7, 8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

(S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7, 8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

(S)-6,6-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6, 8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

Step 1: 7, 7-dimethyloxepan-4-one and 2, 2-dimethyloxepan-4-one

To a solution of 2, 2-dimethyltetrahydropyran-4-one (10.4 g, 81.14 mmol) in dichloromethane (40 mL) and boron fluoride ethyl ether (11.2 mL, 48% ethyl ether) was added (diazomethyl)trimethylsilane (48.0 mL, 96.0 mmol, 2 M in hexane) dropwise at −30° C. After addition, the resulting solution was stirred for 1 h at −30° C. and then quenched by addition of saturated sodium bicarbonate (30 mL). The resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 18% ethyl acetate in petroleum ether) to afford a mixture of 7,7-dimethyloxepan-4-one and 2,2-dimethyloxepan-4-one (2.6 g, 22.5% yield, ratio 1:1) as a pale yellow oil.

Step 2: ethyl 5,5-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate; ethyl 7,7-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate; ethyl 6,6-dimethyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate

To a solution of 7,7-dimethyloxepan-4-one and 2,2-dimethyloxepan-4-one (2.6 g, 18.3 mmol) and pyrrolidine (85 mg, 1.2 mmol) in dimethyl sulfoxide (20 mL) was slowly added ethyl diazoacetate (1.39 g, 12.2 mmol). After addition, the reaction was stirred at 22° C. for 16 h and poured into water (30 mL). The mixture was then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (30 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 18% ethyl acetate in petroleum ether) to afford a mixture of three regio-isomers (900 mg, 20.6% yield) as yellow oil. The regio-isomers were separated by SFC to afford:

Peak 1 (Retention time 3.31 min), ethyl 5,5-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (200 mg): ¹H NMR (400 MHz, CDCl₃) δ 4.38-4.33 (m, 2H), 3.88 (t, J=6.0 Hz, 2H), 3.11 (s, 2H), 2.97 (t, J=6.00 Hz, 2H), 1.37 (t, J=6.00 Hz, 2H), 1.21 (s, 6H) Peak 2 (Retention time 3.37 min), ethyl 7,7-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (150 mg) as a yellow oil: ¹H NMR (400 MHz, CDCl3) δ 4.39-4.34 (m, 2H), 3.92-3.87 (m, 2H), 3.08-3.03 (m, 2H), 2.98 (s, 2H), 1.38 (t, J=6.0 Hz, 3H), 1.23 (s, 6H) Peak 3 (Retention time 6.30 min), ethyl 6,6-dimethyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate (150 mg) as a yellow oil: ¹H NMR (400 MHz, CDCl3) δ 4.68 (s, 2H), 4.40-4.35 (m, 2H), 3.00-2.92 (m, 2H), 1.95-1.88 (m, 2H), 1.39 (t, J=6.0 Hz, 3H), 1.33 (s, 6H).

SFC conditions:

Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min

Flow rate: 2.5 mL/min Column temp.: 35° C.

Column: Chiralpak AY 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: iso-propanol

(0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Step 3: 5,5-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid

To a solution of ethyl 5,5-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (200 mg, 0.84 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (100 mg, 4.20 mmol). The mixture was stirred at 20° C. for 20 h and concentrated to dryness in vacuo. The residue was diluted with water (30 mL) and adjusted to pH=3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 5,5-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid (160 mg, 90.7% yield) as a white solid: LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 3 mins) retention time 1.76 min, ESI+ found [M+H]=211.2.

Step 4: (S)-5,5-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7, 8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

To a solution of 1-hydroxybenzotriazole (54 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (77 mg, 0.40 mmol) 5,5-dimethyl-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxylic acid (70 mg, 0.33 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (70 mg, 0.37 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (26-56% acetonitrile in water and 0.05% ammonia) to afford (S)-5, 5-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4, 5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide (95 mg, 74.9% yield) as a white solid:

¹H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.49-7.47 (m, 1H), 7.35-7.19 (m, 3H), 4.85-4.78 (m, 1H), 4.52-4.46 (m, 1H), 4.41-4.37 (m, 1H), 3.77-3.75 (m, 2H), 3.31 (s, 3H), 3.01 (s, 2H), 2.82-2.79 (m, 2H), 1.04 (s, 6H). LCMS R_(T)=0.80 min, m/z=385.1 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=385.1.

Step 5: 7,7-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid

To a solution of ethyl 7,7-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylate (150 mg, 0.63 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (75 mg, 3.15 mmol). The mixture was stirred at 20° C. for 20 h and concentrated to dryness in vacuo. The residue was diluted with water (20 mL) and adjusted to pH=3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 7,7-dimethyl-4,5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxylic acid (95 mg, 71.8% yield) as a white solid: LCMS R_(T)=1.80 min, m/z=211.2 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 3 mins) retention time 1.80 min, ESI+ found [M+H]=211.2.

Step 6: (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,7, 8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide

To a solution of 1-hydroxybenzotriazole (39.2 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (55.6 mg, 0.29 mmol), 7,7-dimethyl-1,4,5,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxylic acid (50.0 mg, 0.24 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50.3 mg, 0.26 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (26-56% acetonitrile in water and 0.05% ammonia) to afford (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4, 5,7,8-tetrahydro-1H-oxepino[4,5-c]pyrazole-3-carboxamide (65 mg, 70.5% yield) as a white solid:

¹H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.50-7.48 (m, 1H), 7.36-7.19 (m, 3H), 4.85-4.78 (m, 1H), 4.54-4.37 (m, 2H), 3.73-3.71 (m, 2H), 3.31 (s, 3H), 2.89-2.79 (m, 4H), 1.12 (s, 3H), 1.11 (s, 3H). LCMS R_(T)=0.79 min, m/z=385.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=385.1.

Step 7: 6,6-dimethyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid

To a solution of ethyl 6,6-dimethyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylate (100 mg, 0.42 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide (50 mg, 2.10 mmol). The mixture was stirred at 23° C. for 20 h and concentrated to dryness in vacuo. The residue was diluted with water (20 mL) and adjusted to pH=3 by addition of 1 N hydrochloric acid. The solution was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford crude 6,6-dimethyl-4,5,6,8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxylic acid (70 mg, 79.3% yield) as a white solid: LCMS R_(T)=1.86 min, m/z=211.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 3 mins) retention time 1.86 min, ESI+ found [M+H]=211.2.

Step 8: (S)-6,6-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6, 8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide

To a solution of 1-hydroxybenzotriazole (54 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (77 mg, 0.40 mmol), 6,6-dimethyl-1,4,5,8-tetrahydrooxepino[3,4-c]pyrazole-3-carboxylic acid (70 mg, 0.33 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (70 mg, 0.37 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (55-85% methanol in water and 0.05% ammonia) to afford (S)-6,6-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4, 5,6, 8-tetrahydro-1H-oxepino[3,4-c]pyrazole-3-carboxamide (95 mg, 74.9% yield) as a white solid:

¹H NMR (400 MHz, DMSO-d6) δ12.93 (br. s, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.39-7.16 (m, 3H), 4.83-4.81 (m, 1H), 4.61-4.33 (m, 4H), 3.31 (s, 3H), 2.80-2.70 (m, 2H), 1.85-1.70 (m, 2H), 1.20 (s, 6H). LCMS R_(T)=0.81 min, m/z=385.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.81 min, ESI+ found [M+H]=385.1.

Example 27 Method Y

(S)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide and (R)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: N-(1H-pyrazol-3-yl)formamide

A solution of 1H-pyrazol-3-amine (2.5 g, 30.09 mmol) in formic acid (10 mL) was heated to 110° C. for 2 h in a sealed vessel. After this time, the reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% 3:1 isopropyl acetate:methanol in heptane) affording N-(1H-pyrazol-3-yl)formamide (2.75 g, 82%) as a white solid used as is in the next step: LCMS R_(T)=0.25 min, m/z=112 [M+H]⁺.

Step 2: N-methyl 1-H-pyrazol-3-amine

To a solution of N-(1H-pyrazol-3-yl)formamide (2.75 g, 24.8 mmol) in anhydrous tetrahydrofuran (100 mL) cooled to 0° C. under nitrogen was slowly added a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 37.1 mL, 74.3 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and was stirred for 16 h. After this time, the reaction was quenched with solid sodium sulfate decahydrate and stirred at RT for 30 mins. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuo to afford N-methyl-1H-pyrazol-3-amine (1.97 g, 82% yield) as an orange oil used as in the next step without further purification.

Step 3: 4-chloro-N-(1-(4-chlorobutanoyl)-1H-pyrazol-5-yl)-N-methylbutanamide

To a stirred solution of N-methyl-1H-pyrazol-5-amine (200 mg, 2.06 mmol) in anhydrous dichloromethane (10 mL) cooled to 0° C. was added N,N-diisopropylethylamine (1.08 mL, 6.18 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (0.697 g. 4.94 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (0.025 g, 0.21 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was partially concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) affording 4-chloro-N-(1-(4-chlorobutanoyl)-1H-pyrazol-5-yl)-N-methylbutanamide as a colorless oil (0.450 g, 71%) used as is in the next step: LCMS R_(T)=1.35 min, m/z=306 [M+H]⁺.

Step 4: 4-chloro-N-methyl-N-(1H-pyrazol-5-yl)butanamide

To a stirred solution of 4-chloro-N-(1-(4-chlorobutanoyl)-1H-pyrazol-5-yl)-N-methylbutanamide (0.338 g, 1.10 mmol) in ethanol (2 mL) was added sodium hydroxide (1 mol/L) in water (1.10 mL, 1.10 mmol) and the mixture was left to stand at RT for 5 min. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 4-chloro-N-methyl-N-(1H-pyrazol-5-yl)butanamide as a white solid (0.185 g, 83%) used in the next step without further purification: LCMS R_(T)=0.86 min, m/z=202 [M+H]⁺.

Step 5: 4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 4-chloro-N-methyl-N-(1H-pyrazol-5-yl)butanamide (0.185 g, 0.92 mmol) in N,N-dimethylformamide (4 mL) was added cesium carbonate (0.597 g, 1.83 mmol) and stirred at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a viscous colorless oil (0.123 g, 81%) used as is in the next step: LCMS R_(T)=0.76 min, m/z=166 [M+H]⁺.

Step 6: 6-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.123 g, 0.745 mmol) cooled to −78° C. in dry tetrahydrofuran (5 mL) was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 mol/L) in dry tetrahydrofuran (2.23 mL, 2.23 mmol) under nitrogen. The resulting solution was stirred at −78° C. for 30 min and N-bromosuccinimide (0.265, 1.49 mmol) was added and stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated sodium bisulfite (50 mL) and extracted with isopropyl acetate (3×50 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 6-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a pale yellow oil (0.083 g, 460) use as is in the next step: LCMS R_(T)=0.83 min, m/z=244 [M+H]⁺.

Step 7: 6-azido-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 6-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.083 g, 0.30 mmol) in N, N-dimethylformamide (1 mL) was added sodium azide (0.026 g, 0.41 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 6-azido-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a pale orange oil (0.067 g, 96%) used as is in the next step: LCMS R_(T)=0.93 min, m/z=207 [M+H]⁺.

Step 8: 6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 6-azido-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.067 g, 0.32 mmol) in methanol (2 mL) was added 10% Pd/C (0.069 g, 0.065 mmol), a balloon of hydrogen, and the mixture was stirred at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo affording 6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a viscous oil (0.055 g, 94%) used in the next step without further purification: LCMS R_(T)=0.25 min, m/z=181 [M+H]⁺.

Step 9: 5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

To a stirred solution of 6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.055 g, 0.31 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.074 g, 0.37 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.182 g, 0.34 mmol) and N,N-diisopropylethylamine (0.160 mL, 0.92 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (0 to 35% acetonitrile in water and 0.1% formic acid) affording 5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1, 2,4-triazole-3-carboxamide as a white solid (0.029 mg, 26%): ¹H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 8.56 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.38-7.16 (m, 5H), 6.34 (d, J=2.0 Hz, 1H), 4.42-4.13 (m, 3H), 4.11 (s, 2H), 3.24 (s, 3H), 2.69-2.53 (m, 1H), 2.47-2.32 (m, 1H). LCMS R_(T)=3.35 min, m/z=366.2 [M+H]⁺.

Step 10: (S)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide and (R)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1, 2,4-triazole-3-carboxamide was further purified by chiral SFC (ID column, 30% methanol+0.1% ammonium hydroxide isocratic elution) affording arbitrarily assigned enantiomers (S)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (0.012 g, 11%) and (R)-5-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (0.012 g, 11%) as white solids:

Analytical data for the first eluting enantiomer (arbitrarily assigned S configuration): SFC R_(T)(ID column, 30% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.545 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 14.44 (s, 1H), 8.54 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.35-7.20 (m, 5H), 6.34 (d, J=2.0 Hz, 1H), 4.42-4.13 (m, 3H), 4.10 (s, 2H), 3.24 (s, 3H), 2.65-2.53 (m, 1H), 2.44-2.30 (m, 1H). LCMS R_(T)=3.35 min, m/z=366.1 [M+H]⁺. Analytical data for the second eluting enantiomer (arbitrarily assigned R configuration): SFC R_(T): 0.908 min, 99% ee: ¹H NMR (400 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.54 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.43-7.13 (m, 5H), 6.34 (d, J=2.0 Hz, 1H), 4.42-4.13 (m, 3H), 4.10 (s, 2H), 2.67-2.52 (m, 1H), 2.46-2.29 (m, 1H). LCMS R_(T)=3.35 min, m/z=366.2 [M+H]⁺.

Example 28 Method Z

3: 5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: N-(5-methyl-1H-pyrazol-3-yl)formamide

A solution of 5-methyl-1H-pyrazol-3-amine (1.8 g, 18.5 mmol) in formic acid (10 mL) was heated to 110° C. for 3 h in a sealed vessel. After this time, the reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording N-(5-methyl-1H-pyrazol-3-yl)formamide (1.96 g, 85%) as an off-white solid used as is in the next step: LCMS R_(T)=0.50 min, m/z=126 [M+H]⁺.

Step 2: N,5-dimethyl-1H-pyrazol-3-amine

To a solution of N-(5-methyl-1H-pyrazol-3-yl)formamide (1.96 g, 15.7 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0° C. under nitrogen was slowly added a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 23.5 mL, 47.0 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and was stirred for 16 h. After this time, the reaction was quenched with solid sodium sulfate decahydrate and stirred at RT for 30 mins. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuo to afford N,5-dimethyl-1H-pyrazol-3-amine (1.79 g, 103% yield) as a yellow oil used in the next step without further purification.

Step 3: 4-chloro-N-[1-(4-chlorobutanoyl)-5-methyl-pyrazol-3-yl]-N-methyl-butanamide

To a stirred solution of N,5-dimethyl-1H-pyrazol-3-amine (1.74 g, 15.7 mmol) in anhydrous dichloromethane (50 mL) cooled to 0° C. was added N,N-diisopropylethylamine (8.19 mL, 47.0 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (5.3 g, 37.6 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (0.191 g, 1.57 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was partially concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) affording 4-chloro-N-[1-(4-chlorobutanoyl)-5-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.37 g, 47%) as an orange oil used as is in the next step: LCMS R_(T)=1.43 min, m/z=320 [M+H]⁺.

Step 4: 4-chloro-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)butanamide

To a stirred solution of 4-chloro-N-[1-(4-chlorobutanoyl)-5-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.37 g, 7.4 mmol) in ethanol (20 mL) was added sodium hydroxide (1 mol/L) in water (7.4 mL, 7.4 mmol) and the mixture was left to stand at RT for 5 min. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 4-chloro-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)butanamide (1.4 g, 88%) as a yellow oil used in the next step without further purification: LCMS R_(T)=0.99 min, m/z=216 [M+H]⁺.

Step 5: 2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-chloro-N-methyl-N-(5-methyl-1H-pyrazol-3-yl)butanamide (1.4 g, 6.5 mmol) in acetonitrile (10 mL) was added cesium carbonate (3.2 g, 13.0 mmol), and the resulting suspension was stirred at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.655 g, 56%) as a viscous colorless oil used as is in the next step: LCMS R_(T)=0.91 min, m/z=180 [M+H]⁺.

Step 6: 6-iodo-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.655 g, 3.65 mmol) in dry dichloromethane (20 mL) under nitrogen cooled to ˜−10° C. in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (2.55 g, 22 mmol) followed by iodotrimethylsilane (4.4 g, 22 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time was added iodine (2.8 g, 11 mmol). The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was quenched with saturated sodium bisulfite (50 mL). The layers were separated, and the aqueous was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 6-iodo-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a brown solid (0.874 g, 78%) used as is in the next step: LCMS R_(T)=1.03 min, m/z=306 [M+H]⁺.

Step 7: 6-azido-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-iodo-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.874 g, 2.86 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (0.223 g, 3.44 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a pale orange oil (0.606 g, 96%) used as is in the next step: LCMS R_(T)=0.99 min, m/z=221 [M+H]⁺.

Step 8: 6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[,5-a][1,3]diazepin-5-one

To a solution of 6-azido-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.606 g, 2.75 mmol) in tetrahydrofuran (5 mL) was added water (1 mL) followed by polymer-bound triphenylphosphine (2.75 g, ˜3 mmol/g loading). The mixture was shaken at RT for 16 h, filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) affording 6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a colorless oil (0.500 g, 94%) used as is in the next step: LCMS R_(T)=0.54 min, m/z=195 [M+H]⁺.

Step 9: 5-benzyl-N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1, 2,4-triazole-3-carboxamide

To a stirred solution of 6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.029 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.095 g, 0.18 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) affording 6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a white solid (0.029 g, 51%): 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 8.53 (s, 1H), 7.36-7.21 (m, 6H), 6.13 (s, 1H), 4.39-4.21 (m, 2H), 4.18-4.01 (m, 4H), 3.22 (s, 3H), 2.57 (ddd, J=12.8, 8.0, 4.9 Hz, 1H), 2.41-2.29 (m, 1H), 2.17 (s, 3H). LCMS R_(T)=3.58 min, m/z=380.2 [M+H]⁺.

Example 29 Method AA

5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: N-(5-cyclopropyl-1H-pyrazol-3-yl)formamide

A solution of 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16.2 mmol) in formic acid (10 mL) was heated to 110° C. for 3 h in a sealed vessel. After this time, the reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording N-(5-cyclopropyl-1H-pyrazol-3-yl)formamide (1.74 g, 71%) as an off-white solid used as is in the next step: LCMS R_(T)=0.86 min, m/z=152 [M+H]⁺.

Step 2: 5-cyclopropyl-N-methyl-1H-pyrazol-3-amine

To a solution of N-(5-cyclopropyl-1H-pyrazol-3-yl)formamide (1.74 g, 11.5 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0° C. was slowly added a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 17.3 mL, 34.5 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and was stirred for 16 h. After this time, the reaction was quenched with solid sodium sulfate decahydrate and stirred at RT for 30 mins. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuo to afford 5-cyclopropyl-N-methyl-1H-pyrazol-3-amine (1.70 g, 110% yield) as an orange oil used in the next step without further purification.

Step 3: 4-chloro-N-[1-(4-chlorobutanoyl)-5-cyclopropyl-pyrazol-3-yl]-N-methyl-butanamide

To a stirred solution of 5-cyclopropyl-N-methyl-1H-pyrazol-3-amine (0.760 g, 5.5 mmol) in anhydrous dichloromethane (50 mL) cooled to 0° C. was added N,N-diisopropylethylamine (2.90 mL, 16.6 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (1.87 g, 13.3 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (0.068 g, 0.55 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was partially concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) affording 4-chloro-N-[1-(4-chlorobutanoyl)-5-cyclopropyl-pyrazol-3-yl]-N-methyl-butanamide (1.18 g, 62%) as an orange oil used as is in the next step: LCMS R_(T)=1.50 min, m/z=346 [M+H]⁺.

Step 4: 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-methyl-butanamide

To a stirred solution of 4-chloro-N-[1-(4-chlorobutanoyl)-5-cyclopropyl-pyrazol-3-yl]-N-methyl-butanamide (1.18 g, 3.4 mmol) in ethanol (5 mL) was added sodium hydroxide (1 mol/L) in water (3.4 mL, 3.4 mmol) and the mixture was left to stand at RT for 5 min. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-methyl-butanamide (0.540 g, 66%) as a colorless oil used as is in the next step: LCMS R_(T)=1.08 min, m/z=242 [M+H]⁺.

Step 5: 2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-methyl-butanamide (0.540 g, 2.2 mmol) in acetonitrile (10 mL) was added cesium carbonate (1.46 g, 4.5 mmol), and the resulting suspension was stirred at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.332 g, 72%) as a pink oil used as is in the next step: LCMS R_(T)=0.98 min, m/z=206 [M+H]⁺.

Step 6: 6-bromo-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.332 g, 1.6 mmol) cooled to −78° C. in dry tetrahydrofuran (8 mL) was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 mol/L) in anhydrous tetrahydrofuran (3.23 mL, 3.23 mmol) under nitrogen. The resulting solution was stirred at −78° C. for 30 min and N-bromosuccinimide (0.432, 2.42 mmol) was added and stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated sodium bisulfite (50 mL) and extracted with isopropyl acetate (3×50 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 4% methanol in dichloromethane) affording 6-bromo-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a pale yellow oil (0.210 g, 46%) used as is in the next step: LCMS R_(T)=1.06 min, m/z=284 [M+H]⁺.

Step 7: 6-azido-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-bromo-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.210 g, 0.74 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium azide (0.058 g, 0.89 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 6-azido-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a yellow oil (0.109 g, 60%) used as is in the next step: LCMS R_(T)=1.05 min, m/z=247 [M+H]⁺.

Step 8: 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-azido-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.109 g, 0.44 mmol) in tetrahydrofuran (2 mL) was added water (0.4 mL) followed by polymer-bound triphenylphosphine (0.44 g, ˜3 mmol/g loading). The mixture was shaken at RT for 16 h, filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) affording 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a colorless oil (0.096 g, 99%) used as is in the next step: LCMS R_(T)=0.73 min, m/z=221 [M+H]⁺.

Step 9: 5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

To a stirred solution of 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.033 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.095 g, 0.18 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) affording 5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide as a white solid (0.038 g, 62%): 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=7.8 Hz, 1H), 7.36-7.19 (m, 5H), 6.06 (s, 1H), 4.37-4.20 (m, 2H), 4.16-4.02 (m, 3H), 3.20 (s, 3H), 2.65-2.53 (m, 1H), 2.40-2.27 (m, 1H), 1.91-1.80 (m, 1H), 0.92-0.81 (m, 2H), 0.73-0.60 (m, 2H). LCMS R_(T)=3.95 min, m/z=406.2 [M+H]⁺.

Example 30 Method BB

5-benzyl-N-[4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-4H-1,2,4-triazole-3-carboxamide

Step 1: N-[5-(trifluoromethyl)-1H-pyrazol-3-yl]formamide

A solution of 5-(trifluoromethyl)-1H-pyrazol-3-amine (2.3 g, 15.2 mmol) in formic acid (10 mL) was heated to 110° C. for 3 h in a sealed vessel. After this time, the reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording N-[5-(trifluoromethyl)-1H-pyrazol-3-yl]formamide (2.15 g, 79%) as an off-white solid used as is in the next step: LCMS R_(T)=0.85 min, m/z=180 [M+H]⁺.

Step 2: N-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine

To a solution of N-[5-(trifluoromethyl)-1H-pyrazol-3-yl]formamide (2.15 g, 12.0 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0° C. under nitrogen was slowly added a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 18.0 mL, 36.0 mmol) under nitrogen. The reaction mixture was allowed to warm to RT gradually and was stirred for 16 h. After this time, the reaction was quenched with solid sodium sulfate decahydrate and stirred at RT for 30 min. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuo to afford N-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (2.3 g, 120% yield) as an orange oil used in the next step without further purification.

Step 3: 4-chloro-N-methyl-N-[5-(trifluoromethyl)-1H-pyrazol-3-yl]butanamide

To a stirred solution of N-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (2.3 g, 14 mmol) in anhydrous dichloromethane (50 mL) cooled to 0° C. was added N,N-diisopropylethylamine (7.3 mL, 42.0 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (4.7 g, 33 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (0.170 g, 1.4 mmol), and the reaction mixture was stirred at RT 16 h. The reaction mixture was partially concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 4-chloro-N-methyl-N-[5-(trifluoromethyl)-1H-pyrazol-3-yl]butanamide (1.03 g, 27%) as an orange solid used as is in the next step: LCMS R_(T)=1.18 min, m/z=270 [M+H]⁺.

Step 4: 4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-chloro-N-methyl-N-[5-(trifluoromethyl)-1H-pyrazol-3-yl]butanamide (1.0 g, 3.8 mmol) in acetonitrile (10 mL) was added cesium carbonate (2.5 g, 7.7 mmol), and the resulting suspension was stirred at RT for 16 h. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 70% isopropyl acetate in heptane) affording 4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.420 g, 47%) as a yellow solid used as is in the next step: LCMS R_(T)=1.05 min, m/z=234 [M+H]⁺.

Step 5: 6-iodo-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.420 g, 1.80 mmol) in dry dichloromethane (20 mL) under nitrogen cooled to ˜−10° C. in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (1.26 g, 10.8 mmol) followed by iodotrimethylsilane (2.2 g, 10.8 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time was added iodine (1.4 g, 5.4 mmol). The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was quenched with saturated sodium bisulfite (50 mL). The layers were separated, and the aqueous was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% isopropyl acetate in heptane) affording 6-iodo-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a white solid (0.470 g, 73%) used as is in the next step: LCMS R_(T)=1.25 min, m/z=360 [M+H]⁺.

Step 6: 6-azido-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-iodo-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.470 g, 1.3 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (0.102 g, 1.57 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 70% isopropyl acetate in heptane) 6-azido-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a white solid (0.330 g, 92%) used as is in the next step: LCMS R_(T)=1.21 min, m/z=275 [M+H]⁺.

Step 7: 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-azido-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.330 g, 1.2 mmol) in tetrahydrofuran (5 mL) was added water (1 mL) followed by polymer-bound triphenylphosphine (1.2 g, ˜3 mmol/g loading). The mixture was shaken at RT for 16 h, filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) affording 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a colorless oil (0.260 g, 87%) used as is in the next step: LCMS R_(T)=0.89 min, m/z=249 [M+H]⁺.

Step 8: 5-benzyl-N-[4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-4H-1,2,4-triazole-3-carboxamide

To a stirred solution of 6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.037 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.095 g, 0.18 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) affording 5-benzyl-N-[4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-4H-1,2,4-triazole-3-carboxamide as a white solid (0.039 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 8.64 (s, 1H), 7.47-7.13 (m, 5H), 6.93 (s, 1H), 4.53-4.41 (m, 1H), 4.41-4.26 (m, 2H), 4.11 (s, 2H), 3.27 (s, 3H), 2.74-2.57 (m, 1H). LCMS R_(T)=4.33 min, m/z=434.1 [M+H]⁺.

Example 31 Method CC

5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: N-(4-methyl-1H-pyrazol-3-yl)formamide

A solution of 4-methyl-1H-pyrazol-3-amine (1.3 g, 13.4 mmol) in formic acid (10 mL) was heated to 110° C. for 3 h in a sealed vessel. After this time, the reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording N-(4-methyl-1H-pyrazol-3-yl)formamide (1.44 g, 86%) as an off-white solid used as is in the next step: LCMS R_(T)=0.37 min, m/z=126 [M+H]⁺.

Step 2: N,4-dimethyl-1H-pyrazol-3-amine

To a solution of N-(4-methyl-1H-pyrazol-3-yl)formamide (1.44 g, 11.5 mmol) in anhydrous tetrahydrofuran (50 mL) cooled to 0° C. under nitrogen was slowly added a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 17.3 mL, 34.5 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and was stirred for 16 h. After this time, the reaction was quenched with solid sodium sulfate decahydrate and stirred at RT for 30 mins. The resulting mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated in vacuo to afford N,4-dimethyl-1H-pyrazol-3-amine (1.29 g, 101% yield) as a yellow oil used in the next step without further purification.

Step 3: 4-chloro-N-[1-(4-chlorobutanoyl)-4-methyl-pyrazol-3-yl]-N-methyl-butanamide

To a stirred solution of N,4-dimethyl-1H-pyrazol-3-amine (1.28 g, 11.5 mmol) in anhydrous dichloromethane (50 mL) cooled to 0° C. was added N,N-diisopropylethylamine (6.03 mL, 34.6 mmol) followed by dropwise addition of 4-chlorobutanoyl chloride (3.9 g, 27.6 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (0.141 g, 1.15 mmol), and the reaction mixture was stirred at RT 16 h. The reaction mixture was partially concentrated in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 4-chloro-N-[1-(4-chlorobutanoyl)-4-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.2 g, 60%) as an orange oil used as is in the next step: LCMS R_(T)=1.32 min, m/z=320 [M+H]⁺.

Step 4: 4-chloro-N-methyl-N-(4-methyl-1H-pyrazol-3-yl)butanamide

To a stirred solution of 4-chloro-N-[1-(4-chlorobutanoyl)-4-methyl-pyrazol-3-yl]-N-methyl-butanamide (2.2 g, 6.9 mmol) in ethanol (20 mL) was added sodium hydroxide (1 mol/L) in water (6.9 mL, 6.9 mmol) and the mixture was left to stand at RT for 5 min. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 4-chloro-N-methyl-N-(4-methyl-1H-pyrazol-3-yl)butanamide (1.18 g, 80%) as a yellow oil used as is in the next step: LCMS R_(T)=0.99 min, m/z=216 [M+H]⁺.

Step 5: 3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-chloro-N-methyl-N-(4-methyl-1H-pyrazol-3-yl)butanamide (1.47 g, 6.8 mmol) in acetonitrile (20 mL) was added cesium carbonate (8.9 g, 27.2 mmol), and the resulting suspension was stirred at RT for 48 h. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.510 g, 42%) as a viscous white solid used as is in the next step: LCMS R_(T)=0.86 min, m/z=180 [M+H]⁺.

Step 6: 6-iodo-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.450 g, 2.51 mmol) in dry dichloromethane (20 mL) under nitrogen cooled to ˜−10° C. in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (1.75 g, 15.1 mmol) followed by iodotrimethylsilane (3.0 g, 15.1 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time was added iodine (1.91 g, 7.5 mmol). The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was quenched with saturated sodium bisulfite (50 mL). The layers were separated, and the aqueous was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 6-iodo-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a brown solid (0.420 g, 55%) used as is in the next step: LCMS R_(T)=0.99 min, m/z=306 [M+H]⁺.

Step 7: 6-azido-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-iodo-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.420 g, 1.4 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (0.107 g, 1.65 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with isopropyl acetate, filtered through Celite, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 6-azido-3,4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a pale orange oil (0.289 g, 95%) used as is in the next step: LCMS R_(T)=0.80 min, m/z=221 [M+H]⁺.

Step 8: 6-amino-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-azido-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.289 g, 1.31 mmol) in tetrahydrofuran (5 mL) was added water (1 mL) followed by polymer-bound triphenylphosphine (1.31 g, ˜3 mmol/g loading). The mixture was shaken at RT for 16 h, filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) affording 6-amino-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one as a colorless oil (0.146 g, 57%) used as is in the next step: LCMS R_(T)=0.65 min, m/z=195 [M+H]⁺.

Step 9: 5-benzyl-N-(3,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-11, 2,4-triazole-3-carboxamide

To a stirred solution of 6-amino-3,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.029 g, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.095 g, 0.18 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (5 to 50% acetonitrile in water and 0.1% formic acid) affording 5-benzyl-N-(3,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide as a white solid (0.036 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 8.45 (d, J=7.6 Hz, 1H), 7.39-7.12 (m, 6H), 4.40-3.99 (m, 5H), 3.21 (s, 3H), 2.62-2.51 (m, 1H), 2.36-2.21 (m, 1H), 2.01 (s, 3H). LCMS R_(T)=3.61 min, m/z=380.2 [M+H]⁺.

Example 32 Method DD

Step 1: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a stirred solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (0.025 g, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.026 g, 0.16 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.078 g, 0.14 mmol) and N,N-diisopropylethylamine (0.045 mL, 0.26 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (5 to 60% acetonitrile in water and 0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide as a white solid (0.017 g, 38%): ¹H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.52-7.46 (m, 1H), 7.37-7.20 (m, 3H), 4.82 (dt, J=11.3, 7.8 Hz, 1H), 4.49 (dd, J=11.4, 9.8 Hz, 1H), 4.40 (dd, J=9.8, 7.7 Hz, 1H), 3.31 (s, 3H), 2.62-2.53 (m, 4H), 1.75-1.57 (m, 4H). LCMS R_(T)=4.21 min, m/z=341.2 [M+H]⁺.

Example 33 Method EE

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide

To a stirred solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (0.025 g, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added 1H-indazole-3-carboxylic acid (0.026 g, 0.16 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.078 g, 0.14 mmol) and N,N-diisopropylethylamine (0.045 mL, 0.26 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (5 to 60% acetonitrile in water and 0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide as a white solid (0.015 g, 34%): ¹H NMR (400 MHz, DMSO-d6) δ 13.71 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.06 (dt, J=8.2, 1.0 Hz, 1H), 7.63 (dt, J=8.5, 0.9 Hz, 1H), 7.56-7.49 (m, 1H), 7.42 (ddd, J=8.4, 6.9, 1.1 Hz, 1H), 7.38-7.19 (m, 4H), 4.95 (dt, J=11.6, 7.9 Hz, 1H), 4.63 (dd, J=11.6, 9.9 Hz, 1H), 4.47 (dd, J=9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LCMS R_(T)=4.32 min, m/z=337.1 [M+H]⁺.

Example 34 Method FF

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

Step 1: ethyl 2-oxo-2-(2-oxo-5-(trifluoromethyl)cyclohexyl)acetate

To a stirred solution of sodium ethoxide (2.68 mol/L) in ethanol (2.7 mL, 7.2 mmol) cooled to 0° C. was added dropwise a solution of 4-(trifluoromethyl)cyclohexanone (1 g, 6 mmol) in diethyl oxalate (1 g, 7.2 mmol). The reaction mixture was warmed to RT and stirred for 4 h. The reaction was then quenched with an aqueous solution of 5% citric acid (75 mL) and extracted with isopropyl acetate (3×75 mL). The combined organic extracts were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) affording ethyl 2-oxo-2-(2-oxo-5-(trifluoromethyl)cyclohexyl)acetate as a yellow oil (0.623 g, 39%) used as is in the next step: LCMS R_(T)=1.34 min, m/z=267 [M+H]⁺.

Step 2: ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

To a solution of ethyl 2-oxo-2-(2-oxo-5-(trifluoromethyl)cyclohexyl)acetate (0.623 g, 2.34 mmol) in acetic acid (5 mL) was added hydrazine hydrate (300 mg, 4.68 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-H-indazole-3-carboxylate (0.425 g, 69%) as a white solid used as in the next step: LCMS R_(T)=1.23 min, m/z=263 [M+H]⁺.

Step 3: 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

To a solution of ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (0.425 g, 1.62 mmol) in methanol (4 mL) was added sodium hydroxide (1 mol/L) in water (4.05 mL, 4.05 mmol). The reaction mixture was stirred at RT for 16 h. After this time, the mixture was concentrated in vacuo to remove methanol. The remaining solution was added to hydrochloric acid (1 mol/L) in water (50 mL). The resulting precipitate was collected, washed with 1 M hydrochloric acid, and dried thoroughly to afford 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.164 g, 42% yield) as a white solid used in the next step without further purification: LCMS R_(T)=1.03 min, m/z=235 [M+H]⁺.

Step 4: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a stirred solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (0.035 g, 0.18 mmol) in N,N-dimethylformamide (2 mL) was added 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.051 g, 0.22 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.109 g, 0.2 mmol) and N,N-diisopropylethylamine (0.095 mL, 0.55 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (20 to 60% acetonitrile in water and 0.1% formic acid) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4, 5,6,7-tetrahydro-1H-indazole-3-carboxamide (0.037 g, 50%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.53-7.45 (m, 1H), 7.37-7.20 (m, 3H), 4.83 (dt, J=11.5, 8.1 Hz, 1H), 4.52 (ddd, J=11.3, 10.7, 3.9 Hz, 1H), 4.40 (ddd, J=10.0, 7.7, 2.5 Hz, 1H), 3.31 (s, 3H), 2.98 (dt, J=16.0, 4.4 Hz, 1H), 2.85-2.54 (m, 3H), 2.49-2.38 (m, 1H), 2.15-2.01 (m, 1H), 1.71-1.53 (m, 1H). LCMS R_(T)=4.95 min, m/z=409.1 [M+H]⁺.

Step 5: (5S)—N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5, 6,7-tetrahydro-1H-indazole-3-carboxamide and (5R)—N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4, 5,6,7-tetrahydro-1H-indazole-3-carboxamide was further purified by chiral SFC (SFC conditions: Column: Regis Whelk 0-1 (s,s)50×4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 25% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar) affording arbitrarily assigned diastereomers (5S)—N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (0.015 g, 20%) and (5R)—N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-4,5,6, 7-tetrahydro-1H-indazole-3-carboxamide (0.013 g, 17%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T) (Whelk 0-1 (S,S) column, 25% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 1.01 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.68-7.41 (m, 1H), 7.41-7.06 (m, 3H), 4.83 (dt, J=11.4, 7.7 Hz, 1H), 4.51 (dd, J=11.5, 9.8 Hz, 1H), 4.40 (dd, J=9.8, 7.7 Hz, 1H), 3.31 (s, 3H), 2.98 (dd, J=16.0, 5.1 Hz, 1H), 2.86-2.74 (m, 1H), 2.74-2.57 (m, 2H), 2.47-2.37 (m, 1H), 2.16-2.02 (m, 1H), 1.72-1.51 (m, 1H). LCMS R_(T)=4.95 min, m/z=409.1 [M+H]⁺.

Analytical data for the second eluting diastereomer (arbitrarily assigned R,S configuration): SFC R_(T) 1.13 min, 98% ee: ¹H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.63-7.39 (m, 1H), 7.43-7.11 (m, 3H), 4.83 (dt, J=11.4, 7.8 Hz, 1H), 4.52 (dd, J=11.5, 9.8 Hz, 1H), 4.41 (dd, J=9.9, 7.7 Hz, 1H), 3.31 (s, 3H), 2.99 (dd, J=16.0, 5.1 Hz, 1H), 2.85-2.74 (m, 1H), 2.74-2.58 (m, 2H), 2.48-2.38 (m, 1H), 2.16-2.03 (m, 1H), 1.71-1.53 (m, 1H). LCMS R_(T)=4.95 min, m/z=409.1 [M+H]⁺.

Example 35 Method GG

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxamide

Step 1: ethyl 2-oxo-2-[[5-(trifluoromethyl)-2-pyridyl]methylamino]acetate

To a solution of [5-(trifluoromethyl)-2-pyridyl]methanamine (1.0 g, 5.7 mmol) in anhydrous tetrahydrofuran cooled to 0° C. under nitrogen was added triethylamine (1.19 mL, 8.5 mmol) followed by ethyl 2-chloro-2-oxo-acetate (0.85 g, 6.25 mmol). The reaction mixture warmed to RT slowly and stirred for 16 h. The reaction mixture was concentrated to dryness in vacuo and partitioned between isopropyl acetate (100 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated to dryness in vacuo affording ethyl 2-oxo-2-[[5-(trifluoromethyl)-2-pyridyl]methylamino]acetate (1.2 g, 77%) as an orange solid used in the next step without further purification: LCMS R_(T)=1.05 min, m/z=277 [M+H]⁺.

Step 2: ethyl 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate

A suspension of ethyl 2-oxo-2-[[5-(trifluoromethyl)-2-pyridyl]methylamino]acetate (1.2 g, 4.3 mmol) in phosphoryl chloride (12 mL, 129 mmol) was heated to 100° C. for 16 h. The reaction mixture was concentrated to dryness in vacuo, diluted with dichloromethane/methanol/trimethylamine (85:5:10) and purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate as a brown solid (0.460 g, 32%) used as is in the next step: LCMS R_(T)=1.26 min, m/z=259 [M+H]⁺.

Step 3: sodium 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate

To a solution of ethyl 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate (0.100 g, 0.39 mmol) in tetrahydrofuran (2 mL) was added sodium hydroxide (1 mol/L) in water (0.47 mL. 0.47 mmol). The reaction mixture stirred at RT for 16 h, concentrated to dryness in vacuo affording sodium 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate as a brown solid used in the next step without further purification: LCMS R_(T)=0.93 min, m/z=231 [M+H]⁺.

Step 4: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxamide

To a stirred solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.074 g, 0.32 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium 6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxylate (0.097 g, 0.39 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.210 g, 0.39 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by column chromatography (silica gel, 100-200 mesh, 0 to 70% isopropyl acetate in heptane) affording N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxamide as a yellow solid (0.118 g, 91%): ¹H NMR (400 MHz, DMSO-d6) δ 9.66 (p, J=1.2 Hz, 1H), 8.78 (d, J=8.0 Hz, 1H), 8.03 (dt, J=9.6, 0.9 Hz, 1H), 7.81 (d, J=0.8 Hz, 1H), 7.58-7.46 (m, 1H), 7.41-7.19 (m, 4H), 4.91 (dt, J=11.6, 7.8 Hz, 1H), 4.69 (dd, J=11.6, 9.9 Hz, 1H), 4.46 (dd, J=9.9, 7.7 Hz, 1H), 3.33 (s, 3H). LCMS R_(T)=5.64 min, m/z=405.1 [M+H]⁺.

Example 36 Method HH

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide

To a solution of N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6-(trifluoromethyl)imidazo[1,5-a]pyridine-3-carboxamide (0.034 g, 0.084 mmol) in methanol (2 mL) was added palladium hydroxide (10 wt % loading, 0.020 g) followed by a balloon of hydrogen. The reaction mixture was stirred at RT for 16 h, filtered through Celite and concentrated to dryness in vacuo affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-5, 6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide (34 mg, 99%) as a yellow oil: ¹H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=8.0 Hz, 1H), 7.54-7.45 (m, 1H), 7.37-7.19 (m, 3H), 6.89 (d, J=0.8 Hz, 1H), 4.91-4.69 (m, 2H), 4.57 (ddd, J=11.6, 9.8, 3.6 Hz, 1H), 4.40 (ddd, J=9.8, 7.6, 2.0 Hz, 1H), 4.12-4.01 (m, 2H), 3.31 (s, 3H), 3.04-2.92 (m, 1H), 2.84-2.69 (m, 1H), 2.15-2.04 (m, 1H), 1.83-1.67 (m, 1H). LCMS R_(T)=5.07 min, m/z=409.1 [M+H]⁺.

Example 37 Method II

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide

Step 1: ethyl 2-amino-2-[4-(trifluoromethyl)-2-pyridyl]acetate

To a stirred suspension of sodium hydride (95%, 0.631 g, 25 mmol) in N,N-dimethylformamide (50 mL) cooled to 0° C. was added ethyl 2-(benzhydrylideneamino)acetate (5.35 g, 20 mmol). After stirring the reaction for 30 min at 0° C., 2-chloro-4-(trifluoromethyl)pyridine (4 g, 22 mmol) was added. The reaction mixture was warmed to RT and stirred for 4 h. Hydrochloric acid (1 mol/L) in water (50 mL) was added, and the resulting mixture stirred at RT for 3 h. The mixture was diluted with isopropyl acetate (100 mL) and neutralized with saturated aqueous sodium bicarbonate (50 mL). The layers were separated, and the aqueous was extracted with isopropyl acetate (2×100 mL). The combined organics were dried over sodium sulfate, concentrated to dryness in vacuo, and purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording ethyl 2-amino-2-[4-(trifluoromethyl)-2-pyridyl]acetate (0.630 g, 13%) used as is in the next step: LCMS R_(T)=0.93 min, m/z=249 [M+H]⁺.

Step 2: ethyl 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate

To a solution of ethyl 2-amino-2-[4-(trifluoromethyl)-2-pyridyl]acetate (0.630 g, 0.254 mmol) in toluene (5 mL) was added N,N-dimethylformamide dimethyl acetal (0.44 mL, 3.3 mmol), and the resulting mixture was heated to 80° C. in a sealed vessel for 16 h. The reaction mixture was then concentrated to dryness in vacuo and purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) affording ethyl 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate (0.147 g, 22%) as a white solid used as is in the next step: LCMS R_(T)=1.19 min, m/z=259 [M+H]⁺.

Step 3: sodium 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate

To a stirred solution of ethyl 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate (0.147 g, 0.57 mmol) in tetrahydrofuran (2 mL) was added sodium hydroxide (1 mol/L) in water (1.4 mL, 1.4 mmol). The resulting mixture was heated to 50° C. for 6 h, concentrated to dryness in vacuo affording sodium 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate as a white solid used as is in the next step: LCMS R_(T)=0.95 min, m/z=231 [M+H]⁺.

Step 4: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide

To a stirred solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.052 g, 0.23 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium 7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylate (0.069 g, 0.27 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.148 g, 0.27 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.68 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (30 to 70% acetonitrile in water and 0.1% formic acid) affording N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide (0.067 g, 73%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 8.71-8.66 (m, 2H), 8.36-8.25 (m, 2H), 7.55-7.47 (m, 1H), 7.39-7.21 (m, 3H), 7.12 (dd, J=7.4, 1.9 Hz, 1H), 4.92 (dt, J=11.5, 7.8 Hz, 1H), 4.60 (dd, J=11.5, 9.8 Hz, 1H), 4.47 (dd, J=9.8, 7.7 Hz, 1H), 3.33 (s, 3H). LCMS R_(T)=5.03 min, m/z=405.1 [M+H]⁺.

Example 38 Method JJ

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide

To a solution of N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxamide (0.050 g, 0.12 mmol) in methanol (2 mL) was added palladium hydroxide (10 wt % loading, 0.030 g) followed by a balloon of hydrogen. The reaction mixture was stirred at RT for 16 h, filtered through Celite and concentrated to dryness in vacuo affording N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (31 mg, 61%) as a yellow oil: ¹H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.53-7.45 (m, 1H), 7.36-7.20 (m, 3H), 4.81 (dt, J=11.2, 7.9 Hz, 1H), 4.54-4.36 (m, 2H), 4.33-4.23 (m, 1H), 3.95 (tt, J=12.4, 4.4 Hz, 1H), 3.39-3.33 (m, 1H), 3.31 (s, 3H), 3.05-2.86 (m, 1H), 2.80-2.64 (m, 1H), 2.26-2.12 (m, 1H), 1.95-1.78 (m, 1H). LCMS R_(T)=4.46 min, m/z=409.1 [M+H]⁺.

Example 39 Method KK

(5S)—N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide and (5R)—N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

Step 1: (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one and (6R)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-azido-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.500 g, 2.42 mmol) in methanol (10 mL) was added 10% Pd/C (0.258 g, 0.242 mmol), a balloon of hydrogen, and the mixture was stirred at RT for 16 h. The reaction mixture was filtered through Celite, concentrated to dryness in vacuo, and purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) affording 6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.210 g, 48%) as a viscous oil. The resulting compound was further purified by chiral SFC (Chiralpak AD 150×21.2 mm I.D column, 5 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic 25% B for 6.0 min. Flow rate: 70 mL/min Column temperature: 40° C. BPR: 100 bar) affording arbitrarily assigned diastereomers (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.074 g, 17%) and (6R)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.074 g, 17%) as viscous oils used as is in the next step.

Analytical data for the first eluting enantiomer (arbitrarily assigned S configuration): SFC R_(T)(AD column, 25% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.42 min, 98% ee; Analytical data for the second eluting enantiomer (arbitrarily assigned R configuration): SFC R_(T)=0.69 min, 97% ee.

Step 2: (5S)—N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide and (5R)—N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a stirred solution of (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.022 g, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.034 g, 0.15 mmol), ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (0.080 g, 0.15 mmol) and N,N-diisopropylethylamine (0.064 mL, 0.37 mmol). After stirring at RT for 16 h the reaction mixture was loaded directly for purification by RP-HPLC (20 to 60% acetonitrile in water and 0.1% formic acid) affording N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (0.040 g, 83%) as a white solid.

The resulting compound was further purified by chiral SFC (SFC conditions: Column: Lux Cellulose-1 50×4.6 mm I.D., 3 m Mobile phase: A: CO2 B: Methanol (0.1% NH4OH) Isocratic: 20% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar) affording arbitrarily assigned diastereomers (5R)—N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoro methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (0.019 g, 38%) and (5S)—N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoro methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (0.019 g, 38%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (Lux Cellulose-1 column, 25% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 1.23 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.49 (d, J=2.1 Hz, 1H), 6.32 (d, J=2.0 Hz, 1H), 4.42-4.24 (m, 2H), 4.23-4.12 (m, 1H), 3.25 (s, 3H), 3.05-2.93 (m, 2H), 2.84-2.74 (m, 1H), 2.74-2.54 (m, 3H), 2.39-2.25 (m, 1H), 2.15-2.04 (m, 1H), 1.72-1.55 (m, 1H). LCMS R_(T) '² 3.97 min, m/z=397.1 [M+H]⁺.

Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T) 1.59 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 6.33 (d, J=2.0 Hz, 1H), 4.45-4.09 (m, 3H), 3.25 (s, 3H), 3.01 (dd, J=16.0, 5.1 Hz, 1H), 2.87-2.56 (m, 4H), 2.47-2.25 (m, 2H), 2.18-2.02 (m, 1H), 1.74-1.52 (m, 1H). LCMS R_(T)=3.95 min, m/z=397.1 [M+H]⁺.

Examples 40-43 Chiral Separation of Compounds

Supercritical fluid chromatography (SFC) was performed on select compounds of the invention in order to obtail chiral separation of stereoisomers. SFC chiral conditions are as follows. All isolated peaks were arbitrarily assigned.

Example 40

(S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6, 7-tetrahydro-1H-indazole-3-carboxamide and R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6, 7-tetrahydro-1H-indazole-3-carboxamide Prep:

SFC condition: Column: Chiralcel OX 150×21.2 mm I.D., 5 μm Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 45% B in 6 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 2: 4.5 min) and SFC condition: Column: Chiralcel OX 150×21.2 mm I.D., 5 μm Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 45% B in 6 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 1: 4.0 min).

Analytical:

SFC condition: Column: Chiralcel OX 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 40% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 2: 1.200 min) and SFC condition: Column: Chiralcel OX 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 40% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 1: 1.031 min).

Example 41

(S)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4, 5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide and (R)-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide Prep:

SFC condition: Column: Chiralpak AD 150×21.2 mm I.D., 5 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 25% B in 6.0 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 1: 2.6 min) and SFC condition: Column: Chiralpak AD 150×21.2 mm I.D., 5 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 25% B in 6.0 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 2: 3.0 min).

Analytical:

SFC condition: Column: Chiralpak AD 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 20% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 1: 0.862 min) and SFC condition: Column: Chiralpak AD 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 20% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 2: 0.957 min).

Example 42

(S)-5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide and (R)-5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5, 6,7-tetrahydro-1H-indazole-3-carboxamide Prep:

SFC condition: Column: Lux Cellulose-3 150×21.2 mm I.D., 5 m Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 15% B in 6 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 2: 2.5 min) and SFC condition: Column: Lux Cellulose-3 150×21.2 mm I.D., 5 μm Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 15% B in 6 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 1: 2.0 min).

Analytical:

SFC condition: Column: Lux Cellulose-3 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 15% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 2: 0.551 min) and SFC condition: Column: Lux Cellulose-3 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B:Methanol (0.1% NH₄OH) Isocratic: 15% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 1: 0.0.470 min).

Example 43

Prep:

SFC condition: Column: Chiralpak ID 150×21.2 mm I.D., 5 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 40% B in 6 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 1: 2.0 min) and SFC condition: Column: Chiralpak ID 150×21.2 mm I.D., 5 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 40% B in 6 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 2: 3.25 min).

Analytical:

SFC condition: Column: Chiralpak ID 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 30% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 1: 0.888 min) and SFC condition: Column: Chiralpak ID 50×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B: Ethanol (0.1% NH₄OH) Isocratic: 30% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar (Peak 2: 1.424 min).

Examples 44-82 were prepared according to the above procedures and synthetic schemes as shown in Table 1 below.

Example 83

(S)-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide Method B

(33 mg, 59% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 14.23 (s, 1H), 8.68-8.59 (m, 1H), 8.52-8.43 (m, 1H), 7.87-7.74 (m, 2H), 7.58-7.48 (m, 1H), 7.42-7.18 (m, 3H), 5.00-4.88 (m, 1H), 4.73-4.60 (m, 1H), 4.53-4.41 (m, 1H), 3.33 (s, 3H). LC-MS R_(T)=4.57 min, m/z=362.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.57 min, ESI+ found [M+H]=362.1.

Step 1: 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylic acid

In a screw cap vial, ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (70 mg, 0.259 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (0.2 mL). To the reaction was then added lithium hydroxide (0.20 mL, 0.388 mmol) and stirred at RT for 18 h. Upon completion, reaction was concentrated to dryness in vacuo to afford crude 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylic acid (62 mg, 98% yield) used as is in the next step.

Step 2: (S)-6-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide

To a screw cap vial (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (58 mg, 0.255 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (120 mg, 0.316 mmol), and 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylic acid (62 mg, 0.243 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). To the reaction mixture was added trimethylamine (0.136 mL, 0.973 mmol), the vial was capped and stirred at RT for 16 h. The mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording (S)-6-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazol o[4,3-a]pyridine-3-carboxamide (92 mg, 90% yield), used as is in the next step.

Example 84

Step 3: (S)-6-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2, 4]triazolo[4,3-a]pyridine-3-carboxamide

In a microwave vial, (S)-6-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazol o[4,3-a]pyridine-3-carboxamide (92 mg, 0.221 mmol), potassium cyclopropyltrifluoroborate (68.9 mg, 0.442 mmol), palladium(II) acetate (4.96 mg, 0.022 mmol), di(adamantan-1-yl)(butyl)phosphine (12.51 mg, 0.0332 mmol), and cesium carbonate (288.1 mg, 0.884 mmol) were added and purged with N2 for 2 min. To the vial was then added toluene (4.42 ml, 41.8 mmol) and water (0.442 ml, 24.54 mmol) and the reaction was allowed to stir 110° C. for 18 h. The mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording (S)-6-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[,2,4]triazolo[4,3-a]pyridine-3-carboxamide (18 mg, 21% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (d, J=8.0 Hz, 1H), 9.25-9.20 (m, 1H), 7.99 (dd, J=9.7, 1.0 Hz, 1H), 7.72 (dd, J=9.7, 1.8 Hz, 1H), 7.59-7.49 (m, 1H), 7.42-7.22 (m, 3H), 5.02-4.87 (m, 1H), 4.81-4.67 (m, 1H), 4.54-4.41 (m, 1H), 1.79-1.69 (m, 1H), 1.03-0.93 (m, 2H), 0.80-0.69 (m, 2H). LC-MS R_(T)=4.66 min, m/z=378.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.66 min, ESI+ found [M+H]=378.1.

Example 85

Step 1: 1-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method B

To a screw cap vial 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5 (6H)-one (74 mg, 0.298 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (158 mg, 0.417 mmol), 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (76 mg, 0.358 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). To the reaction mixture was added trimethylamine (0.166 mL, 1.19 mmol), the vial was capped and stirred at RT for 16 h. The mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording 1-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (77 mg, 59% yield): ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 7.49-7.19 (m, 5H), 6.93 (s, 1H), 5.49 (s, 2H), 4.51-4.42 (m, 1H), 4.39-4.27 (m, 2H), 3.27 (s, 3H), 2.72-2.59 (m, 1H), 2.48-2.42 (m, 1H). LC-MS R_(T)=4.34 min, m/z=434.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.34 min, ESI+ found [M+H]=434.1.

Example 86

(S)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoro methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Method B

(20 mg, 29% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H), 10.03 (s, 1H), 8.03 (d, J=2 7.6 Hz, 1H), 7.31-7.16 (m, 1H), 7.12-6.96 (m, 1H), 4.95-4.81 (m, 1H), 4.69-4.56 (m, 1H), 4.56-4.44 (m, 1H), 3.10-2.95 (m, 1H), 2.87-2.58 (m, 3H), 2.17-2.03 (m, 1H), 1.72-1.55 (m, 1H).

LC-MS R_(T)=5.03 min, m/z=434.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.03 min, ESI+ found [M+H]=434.1.

Example 87

(R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoro methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Method B

(12 mg, 17% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H), 10.03 (s, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.49-7.12 (m, 1H), 7.12-6.87 (m, 1H), 5.06-4.81 (m, 1H), 4.67-4.55 (m, 1H), 4.55-4.45 (m, 1H), 3.08-2.95 (m, 1H), 2.87-2.59 (m, 3H), 2.20-2.02 (m, 1H), 1.76-1.56 (m, 1H). LC-MS R_(T)=5.01 min, m/z=434.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.01 min, ESI+ found [M+H]=434.1.

Example 88

(S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Method B

(29 mg, 42% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 9.95 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.05-6.93 (m, 1H), 6.93-6.83 (m, 1H), 4.90-4.77 (m, 1H), 4.60-4.51 (m, 1H), 4.49-4.41 (m, 1H), 3.06-2.95 (m, 1H), 2.85-2.74 (m, 1H), 2.74-2.58 (m, 2H), 2.47-2.42 (m, 1H), 2.30 (s, 3H), 2.14-2.09 (m, 1H), 1.70-1.56 (m, 1H). LC-MS R_(T)=5.20 min, m/z=427.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.20 min, ESI+ found [M+H]=427.1.

Example 89

(R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Method B

(19 mg, 27% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 9.95 (s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.07-6.92 (m, 1H), 6.92-6.80 (m, 1H), 4.97-4.74 (m, 1H), 4.63-4.49 (m, 1H), 4.49-4.37 (m, 1H), 3.07-2.94 (m, 1H), 2.87-2.74 (m, 1H), 2.74-2.59 (m, 2H), 2.48-2.42 (m, 1H), 2.30 (s, 3H), 2.18-2.02 (m, 1H), 1.72-1.55 (m, 1H). LC-MS R_(T)=5.19 min, m/z=427.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.19 min, ESI+ found [M+H]=427.1.

Example 90

(S)-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]isothiazole-3-carboxamide Method B

(24 mg, 24% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (d, J=8.0 Hz, 1H), 8.48-8.40 (m, 1H), 8.23-8.14 (m, 1H), 7.59-7.46 (m, 2H), 7.40-7.20 (m, 3H), 4.99-4.86 (m, 1H), 4.72-4.62 (m, 1H), 4.54-4.42 (m, 1H), 3.34 (s, 3H), 2.46 (s, 3H). LC-MS R_(T)=5.97 min, m/z=368.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.97 min, ESI+ found [M+H]=368.1.

Example 91

(S)-1-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method B

(35 mg, 27% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 7.46-7.17 (m, 5H), 6.93 (s, 1H), 5.49 (s, 2H), 4.52-4.43 (m, 1H), 4.39-4.27 (m, 2H), 3.27 (s, 3H), 2.70-2.58 (m, 1H), 2.47-2.42 (m, 1H). LC-MS R_(T)=4.63 min, m/z=434.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.63 min, ESI+ found [M+H]=434.1.

Example 92

(S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide Method B

(13.8 mg, 25% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 13.58 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.78-7.70 (m, 1H), 7.58-7.46 (m, 2H), 7.39-7.22 (m, 3H), 7.16 (dd, J=8.7, 1.7 Hz, 1H), 5.03-4.83 (m, 1H), 4.67-4.57 (m, 1H), 4.52-4.42 (m, 1H), 2.10-1.96 (m, 1H), 1.00-0.91 (m, 2H), 0.68-0.59 (m, 2H). LC-MS R_(T)=5.36 min, m/z=377.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.36 min, ESI+ found [M+H]=377.1.

Example 93 General for all 8 Membered Lactams

5-benzyl-N-(4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-4H-1,2,4-triazole-3-carboxamide

All NMR spectra were recorded in DMSO-d₆/CD₃OD/CDCl₃ solution in 5 mm o.d. tubes [Wilmad NMR tubes (Sigma-Aldrich), 5 mm Thin Wall, 7″ Length] at 300.0 K and were collected on Bruker Avance NMRS-400 at 400 MHz for ¹H. The chemical shifts (δ) are relative to CDCl₃ (CDCl₃=7.26 ppm), d₆-DMSO (d₆-DMSO=2.5 ppm), CD₃OD (CD₃OD=3.3 ppm) and expressed in ppm. The chemical shifts in CDCl₃, d₆-DMSO and CD₃OD are relative to tetramethylsilane (TMS, =0.00 ppm) and expressed in ppm.

All LC-MS were done using following methods;

Column—ZORBAX EXT (4.6×50 mm, 5u), (mobile phase: from 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min, held this mobile phase composition up to 4.0 min and finally back to initial condition in 5.0 min). Flow=1.2 ml/min.

Column—Restek Ultra AQ C18 (30×2.1 mm, 3u), (mobile phase: 98% [0.05% HCOOH in water] and 2% [CH3CN] held for 0.75 min, then to 90% [0.05% HCOOH in water] and 10% [CH3CN] in 1.0 min, further to 2% [0.05% HCOOH in water] and 98% [CH3CN] in 2.0 min, held this mobile phase composition up to 2.25 min and finally back to initial condition in 3.0 min). Flow=1.5 ml/min

Step 1: 5-chloro-N-(1-(5-chloropentanoyl)-1H-pyrazol-5-yl)-N-methylpentanamide

To a stirred solution of N,5-dimethyl-1H-pyrazol-3-amine (0.500 g, 5.15 mmol) in anhydrous dichloromethane (25 mL) cooled to 0° C. was added N,N-diisopropylethylamine (2.0 mL, 15.4 mmol) followed by dropwise addition of 5-chloropentanoyl chloride (1.65 mL, 12.9 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (33.0 mg, 0.515 mmol), and the reaction mixture was stirred at RT for 6 h. The mixture was diluted with dichloromethane (2×125 mL), and washed with saturated sodium bicarbonate (1×100 mL), water (1×100 mL), brine (1×100 mL), dried over sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20 to 30% ethyl acetate in hexane) to afford 5-chloro-N-(1-(5-chloropentanoyl)-1H-pyrazol-5-yl)-N-methylpentanamide (1.3 g, 76%) as a yellow oil: ¹H NMR (400 MHz, DMSO-d₆) D 8.36 (s, 1H); 6.8 (br. s, 1H); 3.69-3.64 (m, 5H); 3.31 (s, 3H); 3.10-3.07 (m, 2H); 2.55 (br. s, 1H); 1.80-1.62 (m, 8H). LCMS R_(T)=3.46 min, m/z=334 (M+H)⁺.

Step 2: 5-chloro-N-methyl-N-(1H-pyrazol-5-yl)pentanamide

To a stirred solution of 5-chloro-N-(1-(5-chloropentanoyl)-1H-pyrazol-5-yl)-N-methylpentanamide (12.5 g, 37.4 mmol) in ethanol (70 mL) was added sodium hydroxide (1.5 g, 37.4 mmol) in water (37 mL) and the mixture was left to stand at RT for 5 min. The reaction mixture was concentrated to dryness in vacuo, diluted with water (200 mL) and extracted with ethyl acetate (3×150 mL). The filtrate was washed with water, brine, dried over sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 50 to 60% ethyl acetate in hexane) to afford 5-chloro-N-methyl-N-(1H-pyrazol-5-yl)pentanamide (6 g, 74%) as a yellow sticky solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (br. s, 1H); 7.75 (s, 1H); 6.22 (s, 1H); 3.55 (br. s, 2H); 3.09 (s, 3H); 2.17 (br. s, 2H); 1.60 (br. s, 4H). LCMS R_(T)=2.45 min, m/z=216.3 (M+H)⁺.

Step 3: 4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 5-chloro-N-methyl-N-(1H-pyrazol-5-yl)pentanamide (5.0 g, 23.2 mmol) in anhydrous acetonitrile (200 mL) was added cesium carbonate (15.11 g, 46.4 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated to dryness in vacuo and the residue was diluted with ethyl acetate (200 mL) and washed with water (2×200 mL), brine (1×100 mL), dried over sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 40 to 50% ethyl acetate in hexane) to afford 4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (3.4 g, 82%) as a yellow solid: 1H NMR (400 MHz, DMSO-d₆) D 7.49 (s, 1H); 6.28 (s, 1H); 4.33-4.28 (m, 1H); 3.78-3.71 (m, 1H); 3.15 (s, 3H); 2.30-2.24 (m, 1H); 1.93-1.88 (m, 2H); 1.67-1.57 (m, 2H); 1.38-1.42 (m, 1H). LCMS R_(T)=1.64 min, m/z=180 (M+H)⁺.

Step 4: 6-iodo-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 5-chloro-N-methyl-N-(1H-pyrazol-5-yl)pentanamide (3.4 g, 19.0 mmol) in dry dichloromethane (100 mL) under nitrogen cooled to ˜−10° C. in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (17.1 mL, 113.8 mmol) followed by iodotrimethylsilane (15.8 mL, 113.8 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time was added iodine (14.44 g, 56.9 mmol). The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was diluted with water (100 mL). The layers were separated, and the aqueous was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with sodium bisulfite (1×150 mL), water (1×100 mL), brine (1×100 mL) and dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to afford 6-iodo-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (5.5 g, 95%) as a light yellow oil, used as is in the next step: ¹H NMR (400 MHz, DMSO-d₆) Q 7.54 (s, 1H); 6.39 (s, 1H); 4.33-4.26 (m, 1H); 4.04-4.00 (m, 1H); 3.78-3.71 (m, 1H); 3.17 (s, 3H); 2.32-2.27 (m, 2H); 1.93-1.61 (m, 2H). LCMS R_(T)=2.63 min, m/z=306 (M+H)⁺.

Step 5: 6-azido-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 6-iodo-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (1.3 g, 4.26 mmol) in N,N-dimethylformamide (15 mL) was added sodium azide (1.10 g, 17.0 mmol), and the reaction mixture was stirred at RT for 17 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×100 mL), brine (1×100 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 30 to 50% ethyl acetate in heptane) affording azido-6-azido-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (0.500 g, 53%) as a yellow solid (0.606 g, 96%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (s, 1H); 6.37 (s, 1H); 4.34-4.29 (m, 1H); 3.87-3.80 (m, 1H); 3.18 (s, 3H); 3.17-3.15 (m, 1H); 2.05-1.95 (m, 3H); 1.68-1.57 (m, 1H). LCMS R_(T)=2.72 min, m/z=221.2 (M+H)⁺.

Step 6: 6-amino-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 6-azido-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (2.2 g, 9.98 mmol) in methanol (50 mL) was added 10% palladium on carbon (1.0 g) under argon. The reaction mixture was stirred under hydrogen (balloon pressure) at RT for 17 h. The reaction mixture was filtered through Celite, the cake washed with 5% methanol in dichloromethane and the combined filtrate was concentrated to dryness in vacuo affording 6-amino-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (1.65 g, 85%) as a vicious brown liquid used as is in the next step: ¹H NMR (400 MHz, DMSO-d₆) D 7.51 (s, 1H); 6.29 (s, 1H); 4.29-4.24 (m, 1H); 3.78-3.71 (m, 1H); 3.17 (s, 3H); 2.74-2.70 (m, 1H); 1.96-1.88 (m, 3H); 1.66-1.60 (m, 3H). LCMS R_(T)=1.42 min, m/z=195.2 (M+H)⁺.

5-benzyl-N-(4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-4H-1,2,4-triazole-3-carboxamide Method B

(58 mg, 75% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.36-7.28 (m, 2H), 7.29-7.21 (m, 3H), 6.36 (d, J=2.0 Hz, 1H), 4.42-4.29 (m, 1H), 4.09 (s, 2H), 3.97-3.80 (m, 2H), 3.21 (s, 3H), 2.07-1.96 (m, 1H), 1.93-1.77 (m, 2H), 1.66-1.53 (m, 1H). LCMS R_(T)=3.61 min, m/z=380.2=(M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.61 min, ESI+ found [M+H]=380.2.

Example 94

1-benzyl-N-(4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method B

(104 mg, 80% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.24 (d, J=7.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.39-7.27 (m, 5H), 6.36 (d, J=2.0 Hz, 1H), 5.47 (s, 2H), 4.42-4.28 (m, 1H), 3.98-3.77 (m, 2H), 3.21 (s, 3H), 2.08-1.95 (m, 1H), 1.92-1.76 (m, 2H), 1.67-1.54 (m, 1H). LCMS R_(T)=3.72 min, m/z=380.2=(M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.72 min, ESI+ found (M+H]=380.2.

Example 95

N-(4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide Method B

(34 mg, 56% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.31-8.20 (m, 1H), 7.59-7.54 (m, 1H), 7.36-7.17 (m, 6H), 6.41-6.32 (m, 1H), 4.47-4.24 (m, 2H), 4.02-3.76 (m, 2H), 3.22 (s, J=2.4 Hz, 3H), 2.05-1.97 (m, 1H), 1.92-1.76 (m, 2H), 1.64-1.58 (m, 4H). LCMS R_(T)=3.85 min, m/z=394.2=(M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.85 min, ESI+ found [M+H]=394.2.

Example 96

5-(4-fluorobenzyl)-N-(4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-4H-1,2,4-triazole-3-carboxamide Method B

(24 mg, 40% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.32-8.22 (m, 1H), 7.61-7.49 (m, 1H), 7.34-7.25 (m, 2H), 7.18-7.09 (m, 2H), 6.41-6.31 (m, 1H), 4.41-4.28 (m, 1H), 4.09 (s, 2H), 3.98-3.79 (m, 2H), 3.21 (s, 3H), 2.08-1.96 (m, 1H), 1.94-1.77 (m, 2H), 1.68-1.52 (m, 1H). LCMS R_(T)=3.72 min, m/z=398.1=(M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.72 min, ESI+ found [M+H]=398.1

Example 97

5-(2,3-difluorobenzyl)-N-(4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-4H-1,2,4-triazole-3-carboxamide Method B

(41 mg, 60% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.34-8.25 (m, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.39-7.27 (m, 1H), 7.23-7.10 (m, 2H), 6.35 (d, J=2.0 Hz, 1H), 4.41-4.29 (m, 1H), 4.17 (s, 2H), 3.97-3.78 (m, 2H), 3.21 (s, 3H), 2.07-1.97 (m, 1H), 1.96-1.77 (m, 2H), 1.67-1.53 (m, 1H). LCMS R_(T)=3.81 min, m/z=4.16.2 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.81 min, ESI+ found [M+H]=416.2

Example 98

(S)-5-(4-fluorobenzyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide Method B

(55 mg, 94% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.57-8.50 (m, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.38-7.24 (m, 2H), 7.20-7.08 (m, 2H), 6.34 (d, J=2.1 Hz, 1H), 4.42-4.25 (m, 2H), 4.24-4.13 (m, 1H), 4.09 (s, 2H), 3.25 (s, 3H), 2.67-2.53 (m, 1H), 2.44-2.29 (m, 1H). LCMS R_(T)=3.63 min, m/z=384.1 (M+H])⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.63 min, ESI+ found [M+H]=384.1.

Example 99

(S)-5-(2,3-difluorobenzyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide Method B

(42 mg, 80% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.62-8.51 (m, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.39-7.28 (m, 1H), 7.23-7.09 (m, 2H), 6.34 (d, J=2.0 Hz, 1H), 4.41-4.26 (m, 2H), 4.23-4.14 (m, 3H), 3.24 (s, 3H), 2.62-2.55 (m, 1H), 2.44-2.33 (m, 1H). LCMS R_(T)=3.71 min, m/z=402.1 (M+H])⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.71 min, ESI+ found [M+H]=402.1.

Example 100

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide Method B

(54 mg, 74% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.36-7.18 (m, 6H), 6.34 (d, J=2.0 Hz, 1H), 4.42-4.26 (m, 4H), 4.24-4.13 (m, 1H), 3.25 (s, 3H), 1.63 (d, J=7.3 Hz, 3H). LCMS R_(T)=3.75 min, m/z=380.2 (M+H])⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.75 min, ESI+ found [M+H]=380.2.

Example 101

(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4-phenoxypicolinamide Method B

(22 mg, 35% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J=7.8 Hz, 1H), 8.62-8.54 (m, 1H), 7.57-7.45 (m, 3H), 7.39-7.30 (m, 2H), 7.27-7.17 (m, 3H), 6.33 (d, J=2.0 Hz, 1H), 4.44-4.14 (m, 3H), 3.25 (s, 3H), 2.74-2.61 (m, 1H), 2.41-2.27 (m, 1H). LCMS R_(T)=4.59 min, m/z=378.2 (M+H])⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.59 min, ESI+ found [M+H]=378.2.

Example 102

5-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,6-hexahydroimidazo[1,5-a][1,3]diazocin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: N-(1H-imidazol-5-yl)formamide

A solution of 3H-imidazol-4-ylamine (7.9 g, 96.2 mmol) in formic acid (32 ml) was heated at 110° C. for 2 h in a sealed vessel. Reaction mass was cooled to RT and concentrated to dryness in vacuo. The residue was co-distillated with methanol (3×60 ml) affording N-(3H-imidazol-4-yl)-formamide (9.0 g, 84.18%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 10.51 (s, 1H), 8.16 (s, 1H), 7.61 (d, J=8.6 Hz, 1H), 6.47 (s, 1H).

Step 2: N-methyl-1H-imidazol-5-amine

To a stirred solution of N-(3H-imidazol-4-yl)-formamide (4.5 g, 40.5 mmol) in tetrahydrofuran (170 mL) at ice cooled condition was added lithium aluminum hydride (2M solution in tetrahydrofuran, 61 mL, 121.6 mmol) very slowly under nitrogen and the reaction mixture was allowed to warm at RT gradually and stirred for 6 h. The reaction was quenched with solid sodium sulfate and stirred at RT for 30 min. The reaction mixture was diluted with ethyl acetate and filtered through Celite bed and the filtrate was concentrated to dryness in vacuo to afford crude N-methyl-1H-imidazol-5-amine (3.17 g, 81%) as colorless liquid, use as is in the next step.

Step 3: 5-chloro-N-(1-(5-chloropentanoyl)-1H-imidazol-5-yl)pentanamide

To a stirred solution of N-methyl-1H-imidazol-5-amine (6.1 g, 62.1 mmol) in anhydrous dichloromethane (300 mL) cooled to 0° C. was added N,N-diisopropylethylamine (32.8 mL, 188.4 mmol) followed by dropwise addition of 5-chloropentanoyl chloride (19.5 mL, 150.7 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (0.767 mg, 6.28 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated to dryness in vacuo and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20 to 25% ethyl acetate in hexane) affording 5-chloro-N-(1-(5-chloropentanoyl)-1H-imidazol-5-yl)pentanamide (17.5 g, 83%) as a yellow oil: LCMS R_(T)=1.67 min, m/z=334.3 [M]⁺, 336.3 [M+2]⁺.

Step 4: 5-chloro-N-(1H-imidazol-5-yl)pentanamide

To a stirred solution of 5-chloro-N-(1-(5-chloropentanoyl)-1H-imidazol-5-yl)pentanamide (17.5 g, 52.4 mmol) in ethanol (105 mL) was added sodium hydroxide (2.1 g, 52.4 mmol) in water (52.5 mL) and the mixture was left to stand at RT for 5 min. The reaction mixture was concentrated to dryness in vacuo, diluted with water (200 mL) and extracted with ethyl acetate (3×150 mL). The filtrate was washed with water, brine, dried over sodium sulphate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 45 to 50% ethyl acetate in hexane) to afford 5-chloro-N-(1H-imidazol-5-yl)pentanamide (8.8 g, 78%) as a yellow oil: ¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (s, 1H), 7.75 (s, 1H), 6.22 (s, 1H), 3.56 (br. s, 2H), 3.09 (s, 3H), 2.17 (s, 1H), 1.99 (br. s, 2H), 1.60 (br. s, 4H). LCMS R_(T)=2.57 min, m/z=216.1 (M+H)⁺.

Step 5: 1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one

To a solution of 5-chloro-N-(1H-imidazol-5-yl)pentanamide (8.8 g, 40.8 mmol) in anhydrous acetonitrile (350 mL) was added cesium carbonate (26.6 g, 81.6 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography (silica gel, 100-200 mesh, 45 to 50% ethyl acetate in hexane) to afford 1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (5.6 g, 77%) as yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (s, 1H), 6.28 (s, 1H), 4.30 (br. d, J=14.09 Hz), 3.75 (t, J=12.1 Hz, 1H), 3.15 (s, 3H), 2.29-2.25 (m, 1H), 1.93-1.89 (m, 2H), 1.67-1.55 (m, 2H), 1.44-1.38 (m, 1H). LCMS R_(T)=1.90 min, m/z=180.2 (M+H)⁺.

Step 6: 3-iodo-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one

To a solution of 1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (0.730 mg, 4.1 mmol) in dry dichloromethane (65 mL) under nitrogen cooled to ˜−10° C. in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (6.5 mL, 24.4 mmol) followed by iodotrimethylsilane (3.5 mL, 24.4 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time was added iodine (3.1 g, 12.2 mmol). The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was diluted with water (100 mL). The layers were separated, and the aqueous was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with sodium bisulfite (1×150 mL), water (1×100 mL), brine (1×100 mL) and dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to afford 3-iodo-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (1.15 g, 93% crude yield) as a light yellow solid, used as is in the next step: ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (s, 1H), 6.42-6.39 (s, 1H), 4.29 (dd, J=14.6, 3.9 Hz, 1H), 4.06-3.98 (m, 1H), 3.78-3.71 (m, 2H), 3.16 (s, 3H), 2.31-2.26 (s, 2H), 1.84-1.81 (m, 1H), 1.72-1.61 (m, 1H). LCMS R_(T)=2.54 min, m/z=306.1 (M+H)⁺.

Step 7: 3-azido-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one

To a solution of 3-iodo-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (1.1 g, 3.61 mmoL crude) in N,N-dimethylformamide (15 mL) was added sodium azide (0.94 g, 14.4 mmol), and the reaction mixture was stirred at RT for 17 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×100 mL), brine (1×100 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 25 to 30% ethyl acetate in hexane) affording 3-azido-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (0.600 g, 76%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (s, 1H), 6.38 (s, 1H), 4.32 (d, J=14.7 Hz, 1H), 3.84 (t, J=12.2 Hz, 1H), 3.22 (s, 3H), 3.21-3.17 (m, 1H), 2.05-1.98 (m, 3H), 1.26-1.23 (m, 1H). LCMS R_(T)=1.33 min, m/z=221.3 (M+H)⁺.

Step 8: 3-amino-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one

To a solution of 3-azido-1-methyl-3,4, 5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (0.400 mg, 1.82 mmol) in methanol (12 mL) was added 10% palladium on carbon (0.200 g) under argon. The reaction mixture was stirred under hydrogen (balloon pressure) at RT for 3 h. The reaction mixture was filtered through Celite, the cake washed with methanol and the combined filtrate was concentrated to dryness in vacuo affording 3-amino-1-methyl-3,4,5,6-tetrahydroimidazo[1,5-a][1,3]diazocin-2(1H)-one (0.27 mg, 77%) as a light yellow liquid used as is in the next step: ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (s, 1H), 6.30 (s, 1H), 4.27 (dd, J=14.4, 5.3 Hz, 1H), 3.75 (t, J=11.3 Hz, 1H), 3.17 (s, 3H), 2.73-2.67 (m, 1H), 1.99-1.87 (m, 2H), 1.661.47 (m, 3H). LCMS R_(T)=3.64 min, m/z=195.1 (M+H)⁺.

Step 9: 5-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,6-hexahydroimidazo[1,5-a][1,3]diazocin-3-yl)-4H-1,2,4-triazole-3-carboxamide Method B

(19.6 mg, 25% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.31-8.21 (m, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.37-7.18 (m, 5H), 6.59 (s, OH), 6.36 (d, J=2.0 Hz, 1H), 4.41-4.29 (m, 1H), 4.09 (s, 2H), 3.98-3.76 (m, 2H), 3.21 (s, 3H), 2.06-1.98 (m, 1H), 1.93-1.79 (m, 2H), 1.68-1.52 (m, 1H). LCMS R_(T)=3.46 min, m/z=380.2 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.46 min, ESI+ found [M+H]=380.2.

Example 103

1-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,6-hexahydroimidazo[1,5-a][1,3]diazocin-3-yl)-1H-1,2,4-triazole-3-carboxamide Method B

(44 mg, 56% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.24 (d, J=7.1 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.42-7.26 (m, 6H), 6.36 (d, J=2.0 Hz, 1H), 5.47 (s, 2H), 4.42-4.29 (m, 1H), 3.97-3.76 (m, 2H), 3.21 (s, 3H), 2.07-1.97 (m, 1H), 1.92-1.77 (m, 2H), 1.68-1.53 (m, 1H). LCMS R_(T)=3.55 min, m/z=380.2 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.55 min, ESI+ found [M+H]=380.2.

Example 104

1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 5-chloro-N-(1-(5-chloropentanoyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide

To a stirred solution of N,5-dimethyl-1H-pyrazol-3-amine (6 g, 43.7 mmol) in anhydrous dichloromethane (300 mL) cooled to 0° C. was added N,N-diisopropylethylamine (22.8 mL, 131.2 mmol) followed by dropwise addition of 5-chloropentanoyl chloride (13.5 mL, 104.96 mmol) under nitrogen. To the resulting mixture was added 4-dimethylaminopyridine (0.534 mg, 4.37 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated to dryness in vacuo to afford 5-chloro-N-(1-(5-chloropentanoyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide (1.3 g, 76%) as a yellow oil used as is in the next step: LCMS R_(T)=1.79 min, m/z=374.1 (M)⁺, 376.1 (M+2)⁺.

Step 2: 5-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide

To a stirred solution of 5-chloro-N-(1-(5-chloropentanoyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide (21.5 g, crude) in ethanol (115 mL) was added sodium hydroxide (2.29 g, 57.4 mmol) in water (57.6 mL) and the mixture was left to stand at RT for 5 min. The reaction mixture was concentrated to dryness in vacuo, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 45 to 50% ethyl acetate in hexane) to afford 5-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide (4.2 g, 34%) as a yellow oil, used as is in the next step: ¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 5.89 (s, 1H), 3.56 (br. s, 2H), 3.04 (s, 3H), 2.18 (br. s, 2H), 1.87 (br.s, 1H), 1.61-1.57 (m, 4H), 0.92 (d, J=6 Hz, 2H), 0.69 (br. s, 2H). LCMS R_(T)=1.49 min, m/z=256 (M)⁺, 258 (M+2)⁺.

Step 3: 2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 5-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylpentanamide (4.2 g, 19.47 mmol) in anhydrous acetonitrile (200 mL) was added cesium carbonate (12.69 g, 38.95 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography (silica gel, 100-200 mesh, 45 to 50% ethyl acetate in hexane) to afford 2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (3.5 g, 82%) as an off white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 5.99 (s, 1H), 4.30 (br. d, J=10.04 Hz), 3.64 (t, J=12.32 Hz, 1H), 3.11 (s, 3H), 2.27-2.22 (m, 1H), 1.87-1.78 (m, 3H), 1.69 (t, J=11.8 Hz), 1.54-1.51 (m, 1H), 1.39-1.33 (m, 1H) 0.85-0.82 (m, 2H), 0.63 (br. S, 2H).

LCMS R_(T)=1.39 min, m/z=220.0 (M+H)⁺.

Step 4: 2-cyclopropyl-6-iodo-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (2.5 g, 11.4 mmol) in dry dichloromethane (65 mL) under nitrogen cooled to ˜−10° C. in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (18.2 mL, 68.4 mmol) followed by iodotrimethylsilane (9.7 mL, 68.4 mmol). The resulting solution was stirred in the salt/ice bath for 1.5 h, after which time was added iodine (8.6 g, 34.2 mmol). The mixture continued to stir in the salt/ice bath for another 2 h, after which time the reaction mixture was diluted with water (100 mL). The layers were separated, and the aqueous was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with sodium bisulfite (1×150 mL), water (1×100 mL), brine (1×100 mL) and dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to afford 2-cyclopropyl-6-iodo-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (4 g, crude yield) as a light yellow oil, used as is in the next step.

Step 4: 6-azido-2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 2-cyclopropyl-6-iodo-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (4 g, 15.4 mmoL crude) in N,N-dimethylformamide (60 mL) was added sodium azide (3 g, 65.0 mmol), and the reaction mixture was stirred at RT for 17 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×100 mL), brine (1×100 mL), dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 25 to 30% ethyl acetate in hexane) affording 6-azido-2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (2 g, 66% over two steps) as a yellow solid (0.606 g, 96%): ¹H NMR (400 MHz, DMSO-d₆) δ 6.08 (s, 1H), 4.20 (dd, J=14.8, 5.2 Hz, 1H), 3.72 (dd, J=14.8, 11.5 Hz, 1H), 3.30-3.17 (m, 1H), 3.18 (s, 3H), 1.99-1.92 (m, 3H), 1.95 (s, 2H), 1.85-1.80 (m, 1H), 1.65-1.60 (m, 1H), 0.85 (dd, J=8.4, 2.4 Hz, 3H), 0.64 (dd, J=7.4, 5.1 Hz, 2H). LCMS R_(T)=1.51 min, m/z=261.1 (M+H)⁺.

Step 5: 6-amino-2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one

To a solution of 6-azido-2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (3 g, 11.5 mmol) in methanol (50 mL) was added 10% palladium on carbon (1.5 g) under argon. The reaction mixture was stirred under hydrogen (balloon pressure) at RT for 3 h. The reaction mixture was filtered through Celite, the cake washed with methanol and the combined filtrate was concentrated to dryness in vacuo affording 6-amino-2-cyclopropyl-4-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a][1,3]diazocin-5(4H)-one (2.2 g, 82%) as a viscous yellow liquid used as is in the next step: ¹H NMR (400 MHz, DMSO-d₆) δ 6.00 (s, 1H), 4.15 (dd, J=14.2, 4.9 Hz, 1H), 3.64 (dd, J=14.2, 11.4 Hz, 1H), 3.13 (s, 3H), 2.74 (d, J=7.3 Hz, 1H), 1.95 (s, 1H), 1.83-1.82 (m, 2H), 1.63-1.52 (m, 3H), 0.85 (d, J=6.5 Hz, 2H), 0.63 (s, 2H). LCMS R_(T)=2.12 min, m/z=235.2 (M+H)⁺.

Step 6: 1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method B

(29 mg, 65% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.21 (d, J=7.1 Hz, 1H), 7.39-7.24 (m, 5H), 6.07 (s, 1H), 5.47 (s, 2H), 4.32-4.15 (m, 1H), 3.98-3.67 (m, 2H), 3.17 (s, 3H), 2.03-1.72 (m, 4H), 1.67-1.50 (m, 1H), 0.93-0.79 (m, 2H), 0.77-0.53 (m, 2H). LCMS R_(T)=4.11 min, m/z=420.2 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.11 min, ESI+ found [M+H]=420.2.

Example 105

5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,3]diazocin-6-yl)-4H-1,2,4-triazole-3-carboxamide Method B

(8.4 mg, 19% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, OH), 8.28-8.17 (m, 1H), 7.42-7.18 (m, 4H), 6.68 (s, 1H), 6.07 (s, 1H), 4.29-4.18 (m, 1H), 4.09 (s, 2H), 3.93-3.72 (m, 2H), 3.17 (s, 3H), 2.03-1.74 (m, 4H), 1.65-1.50 (m, 1H), 0.91-0.81 (m, 2H), 0.71-0.56 (m, 2H). LCMS R_(T)=3.97 min, m/z=420.2 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.97 min, ESI+ found [M+H]=420.2.

Example 106

1-methyl-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide Method B

(50 mg, 71% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.94-8.88 (m, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 6.35 (d, J=2.0 Hz, 1H), 5.19-5.11 (m, 2H), 4.45-4.33 (m, 2H), 4.31-4.16 (m, 1H), 3.27 (s, 3H), 3.14-3.03 (m, 1H), 2.99-2.87 (m, 1H), 2.78-2.62 (m, 1H), 2.41-2.29 (m, 1H), 1.50 (s, 3H). LCMS R_(T)=4.22 min, m/z=424.1 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.22 min, ESI+ found [M+H]=424.1.

Example 107

1-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method B

(50 mg, 64% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.41 (d, J=7.7 Hz, 1H), 7.44-7.25 (m, 6H), 5.48 (s, 2H), 4.34-4.12 (m, 3H), 3.21 (s, 3H), 2.61-2.53 (m, 1H), 2.29-2.19 (m, 1H), 2.01 (s, 3H). LCMS R_(T)=3.71 min, m/z=380.2 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.71 min, ESI+ found [M+H]=380.2.

Example 108

5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1-[1,3]diazepino[1,2-b]indazol-3-yl)-4H-1,2,4-triazole-3-carboxamide

5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-4H-1, 2,4-triazole-3-carboxamide was prepared from 1H-indazole-3-amine according to Method Z. Yield of final step: 0.057 g, 70%: ¹H NMR (400 MHz, DMSO-d6) δ 7.76 (dt, J=8.5, 1.0 Hz, 1H), 7.62 (dt, J=8.8, 0.9 Hz, 1H), 7.38-7.18 (m, 6H), 7.12 (ddd, J=8.5, 6.6, 0.9 Hz, 1H), 4.61 (dd, J=10.7, 4.1 Hz, 2H), 4.22 (dt, J=11.4, 8.0 Hz, 1H), 4.11 (s, 2H), 3.47 (s, 3H), 2.18 (t, J=7.4 Hz, 1H), 1.47 (d, J=7.5 Hz, 1H). LC-MS R_(T)=4.08 min, m/z=416.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.08 min, ESI+ found [M+H]=416.2.

Example 109

Method G2 5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: methyl 4-[2-(methylamino)benzimidazol-1-yl]butanoate

To a solution of N-methyl-1H-benzimidazol-2-amine (1.36 g, 9.24 mmol, 1.00) in acetonitrile (40 mL) was added cesium carbonate (12 g, 37.0 mmol, 4 equiv) followed by methyl 4-bromobutanoate (1.40 mL, 2.01 g, 11.1 mmol, 1.0 equiv). The reaction mixture was stirred overnight at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford methyl 4-[2-(methylamino)benzimidazol-1-yl]butanoate (0.65 g, 28%) as an orange oil.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.88 min, ESI+ found [M+H]=248.

Step 2: 1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one

To a solution of methyl 4-[2-(methylamino)benzimidazol-1-yl]butanoate (0.650 g, 2.63 mmol) in methanol (3 mL) was added a solution of 1M aqueous sodium hydroxide (2.89 mL, 2.891 mmol, 1.100 equiv). The reaction mixture stirred at RT for 1 h. The mixture was concentrated to dryness in vacuo and resuspended in N,N-dimethylformamide (5 mL), and to it was added N,N-diisopropylethylamine (1.38 mL, 7.89 mmol, 3 equiv) followed by (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.71 g, 3.15 mmol, 1.2 equiv). The reaction stirred 4 h at RT. The reaction mixture was diluted with isopropyl acetate (50 mL), then washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to afford the product 1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.41 g, 72%) as a yellow solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.96 min, ESI+ found [M+H]=216.

Step 3: 3-iodo-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one

To a solution of 1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.375 g, 1.74 mmol) in dichloromethane (10 mL) cooled in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (1.58 mL, 10.45 mmol, 6 equiv) followed by iodotrimethylsilane (1.491 mL, 10.45 mmol, 6 equiv). The reaction mixture was stirred for 1.5 h in the salt/ice bath, then was added iodine (1.33 g, 5.23 mmol, 3 equiv), and the mixture was stirred in the cooling bath for another 2 h. The reaction was then quenched by the addition of a saturated sodium sulfite solution (50 mL). The layers were separated, and the aqueous was extracted two more times with dichloromethane (2×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) to afford 3-iodo-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.445 g, 75% yield) as a white solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.06 min, ESI+ found [M+H]=342.

Step 4: 3-azido-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one

To a solution of 3-iodo-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.45 mg, 1.30 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (0.101 g, 1.57 mmol, 1.2 equiv). The reaction mixture was stirred for 2 h at RT, filtered through Celite, and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) to afford 3-azido-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.315 g, 94%) as a white solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.04 min, ESI+ found [M+H]=257.

Step 5: 3-amino-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one

To a solution of 3-azido-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.315 g, 1.23 mmol, 1 equiv) in tetrahydrofuran (5 mL) was added water (1 mL) and polystyrene-bound triphenylphosphine resin (1.23 g, ˜3 mmol/g loading, 3.69 mmol, 3 equiv). The reaction mixture was shaken for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) to afford 3-amino-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.197 g, 70%) as a colorless oil.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.76 min, ESI+ found [M+H]=231.

Step 6: 5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

To a solution of 3-amino-1-methyl-4, 5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one (0.028 g, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (0.037 g, 0.18 mmol, 1.5 equiv), N,N-diisopropylamine (0.064 mL, 0.047 g, 0.36 mmol, 3 equiv), and (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.076 mg, 0.14 mmol, 1.15 equiv). The reaction mixture was stirred for 16 h at RT, diluted with isopropyl acetate (25 mL), washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative RP-HPLC (5 to 50% acetonitrile in H2O+0.1% formic acid) to afford 5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (0.014 g, 27%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 14.32 (s, 1H), 8.61 (s, 1H), 7.67-7.58 (m, 2H), 7.36-7.19 (m, 7H), 4.72-4.61 (m, 1H), 4.49 (dt, J=11.5, 7.8 Hz, 1H), 4.19-3.98 (m, 3H), 3.42 (s, 3H), 2.76-2.60 (m, 1H), 2.61-2.51 (m, 1H). LC-MS R_(T)=3.97 min, m/z=416.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.97 min, ESI+ found [M+H]=416.2.

Example 110

1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-1H-1, 2,4-triazole-3-carboxamide was prepared from 1H-indazole-3-amine according to Methods Z and G1. Yield of final step: 0.033 g, 52%: ¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.57 (d, J=7.7 Hz, 1H), 7.76 (dt, J=8.5, 1.0 Hz, 1H), 7.62 (dt, J=8.8, 0.9 Hz, 1H), 7.43-7.25 (m, 6H), 7.12 (ddd, J=8.5, 6.6, 0.9 Hz, 1H), 5.47 (s, 2H), 4.65-4.56 (m, 2H), 4.22 (dt, J=11.5, 7.9 Hz, 1H), 3.47 (s, 3H), 2.79-2.65 (m, 1H), 2.61-2.51 (m, 1H). LC-MS R_(T)=4.26 min, m/z=416.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.26 min, ESI+ found [M+H]=416.2.

Example 111

1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[4, 5]imidazo[1,2-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide was prepared from 3-amino-1-methyl-4,5-dihydro-3H-[1,3]diazepino[1,2-a]benzimidazol-2-one according to Method G1. Yield: 0.011 g, 22%: ¹H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.69 (d, J=7.6 Hz, 1H), 7.68-7.56 (m, 2H), 7.43-7.17 (m, 8H), 5.49 (s, 2H), 4.71-4.60 (m, 1H), 4.48 (dt, J=11.5, 7.7 Hz, 1H), 4.05 (ddd, J=14.6, 12.8, 6.5 Hz, 1H), 3.42 (s, 3H), 2.76-2.62 (m, 1H), 2.56-2.45 (m, 1H). LC-MS R_(T)=4.08 min, m/z=416.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.08 min, ESI+ found [M+H]=416.2.

Example 112 Method G3

(S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide

Step 1: 1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (0.029 g, 0.13 mmol, 1 equiv) in N,N-dimethylformamide (2 mL) was added 1-benzyltriazole-4-carboxylic acid (0.040 g, 0.20 mmol, 1.5 equiv), N,N-diisopropylethylamine (0.069 mL, 0.40 mmol, 3 equiv), and (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.082 g, 0.15 mmol, 1.15 equiv). The reaction mixture was stirred overnight, then was diluted with isopropyl acetate (25 mL), washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative RP-HPLC (5 to 50% acetonitrile in H2O+0.1% formic acid) to afford 1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide (0.030 g, 56% yield) as a white solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.46 min, ESI+ found [M+H]=406.2

1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide was further purified by chiral SFC (Whelk 0-1 column, 40% methanol+0.1% ammonium hydroxide isocratic elution) affording arbitrarily assigned enantiomers (R)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide (0.014 g, 26%) and (S)-5-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide (0.013 g, 24%) as white solids:

Analytical data for the first eluting enantiomer (arbitrarily assigned R configuration): SFC R_(T)(Whelk 0-1 column, 40% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.773 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.60 (d, J=7.9 Hz, 1H), 7.54-7.15 (m, 5H), 6.05 (s, 1H), 5.65 (s, 2H), 4.39-4.19 (m, 3H), 4.09 (ddd, J=14.6, 12.6, 6.5 Hz, 1H), 3.19 (s, 3H), 2.62-2.52 (m, 1H), 2.40-2.28 (m, 1H), 1.85 (tt, J=8.4, 5.0 Hz, 1H), 0.89-0.81 (m, 2H), 0.75-0.58 (m, 2H) LCMS R_(T)=4.46 min, m/z=406.2 (M+H)⁺.

Analytical data for the second eluting enantiomer (arbitrarily assigned S configuration): SFC R_(T): 0.960 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.60 (d, J=7.9 Hz, 1H), 7.56-7.18 (m, 5H), 6.05 (s, 1H), 5.65 (s, 2H), 4.46-4.16 (m, 2H), 4.16-3.97 (m, 1H), 3.19 (s, 3H), 2.62-2.52 (m, 1H), 2.42-2.28 (m, 1H), 1.85 (tt, J=8.4, 5.0 Hz, 1H), 0.91-0.80 (m, 2H), 0.73-0.59 (m, 2H). LCMS R_(T)=4.42 min, m/z=406.2 (M+H)⁺.

Example 113 Method G4

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide

Step 1: [5-(trifluoromethyl)-2-pyridyl]hydrazine

To a solution of 2-chloro-5-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol) in ethanol (10 mL) in a large microwave vial was added hydrazine hydrate (1.25 mL, 22 mmol, 4 equiv). The vial was capped and heated in a microwave to 150° C. for 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to afford [5-(trifluoromethyl)-2-pyridyl]hydrazine (0.95 g, 97%) as a tan solid, which was used in the next step without further purification.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.77 min, ESI+ found [M+H]=178.

Step 2: ethyl 2-oxo-2-[2-[5-(trifluoromethyl)-2-pyridyl]hydrazino]acetate

To a solution of [5-(trifluoromethyl)-2-pyridyl]hydrazine (0.95 mg, 5.4 mmol) in tetrahydrofuran (25 mL) cooled to 0° C. was added N,N-diisopropylethylamine (1.87 mL, 10.7 mmol, 2 equiv) followed by ethyl 2-chloro-2-oxo-acetate (0.66 mL, 5.9 mmol, 1.1 equiv). The reaction mixture was allowed to slowly warm to RT with stirring for 16 h. The mixture was concentrated to dryness in vacuo and purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 2-oxo-2-[2-[5-(trifluoromethyl)-2-pyridyl]hydrazino]acetate (0.63 g, 42%) as an orange solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.15 min, ESI+ found [M+H]=278.

Step 3: ethyl 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

A suspension of ethyl 2-oxo-2-[2-[5-(trifluoromethyl)-2-pyridyl]hydrazino]acetate (0.63 g, 2.27 mmol) in phosphoryl chloride (6 mL, 64.6 mmol, 28.4 equiv) was heated to 100° C. for 16 h. The reaction mixture was cooled to RT and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% iPrOAc in heptane) affording ethyl 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.266 g, 45%) as an off-white solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.23 min, ESI+ found [M+H]=260.

Step 4: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide

To a solution of ethyl 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.266 g, 1.02 mmol) dissolved in tetrahydrofuran (4 mL) was added 1M aqueous sodium hydroxide (1.23 mL). The reaction mixture was stirred for 1 h at RT, then concentrated to dryness in vacuo. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.040 g, 0.18 mmol), N,N-diisopropylethylamine (0.092 mL, 0.067 g, 0.52 mmol), and (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.114 g, 0.21 mmol). The reaction mixture was stirred for 16 h at RT, then was purified directly by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1, 2,4]triazolo[4,3-a]pyridine-3-carboxamide (0.035 g, 49%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 9.49-9.40 (m, 2H), 8.25-8.14 (m, 1H), 7.83 (dd, J=9.6, 1.8 Hz, 1H), 7.58-7.49 (m, 1H), 7.40-7.19 (m, 3H), 4.95 (dt, J=11.6, 7.8 Hz, 1H), 4.76 (dd, J=11.7, 9.9 Hz, 1H), 4.47 (dd, J=9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LC-MS R_(T)=4.09 min, m/z=406.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.09 min, ESI+ found [M+H]=406.1

Method G5

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide

To a solution of (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1, 2,4]triazolo[4,3-a]pyridine-3-carboxamide (0.046 g, 0.11 mmol) in methanol (2 mL) was added palladium hydroxide (10 wt %, 0.024 g, 0.017 mmol, 0.15 equiv). The reaction mixture stirred under a balloon of hydrogen gas for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-5, 6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (0.034 g, 73%) as a white solid: 10 ¹H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=8.0 Hz, 1H), 7.55-7.47 (m, 1H), 7.37-7.20 (m, 3H), 4.89-4.79 (m, 1H), 4.72-4.54 (m, 2H), 4.41 (ddd, J=9.8, 7.6, 3.4 Hz, 1H), 4.06 (dd, J=13.3, 10.4 Hz, 1H), 3.31 (s, 3H), 3.23-3.05 (m, 2H), 3.00-2.86 (m, 1H), 2.22-2.10 (m, 1H), 1.99-1.83 (m, 1H). LC-MS R_(T)=4.56 min, m/z=410.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.56 min, ESI+ found [M+H]=410.1

Example 114 Method G6

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(perfluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide

Step 1: ethyl 6-(1,1,2,2,2-pentafluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate

To a solution of ethyl 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (0.2 g, 0.88 mmol) in N,N-dimethylformamide (2 mL) was added (1,1,2,2,2-Pentafluoroethyl)(1,10-phenanthroline-κN1, κN10)copper (0.384 g, 1.06 mmol, 1.2 equiv). The reaction mixture was heated to 90° C. for 24 h, then was diluted with isopropyl acetate (25 mL) and water (25 mL).

The layers were separated, and the aqueous was extracted two more times with isopropyl acetate (2×25 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 6-(1,1,2,2,2-pentafluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (0.031 g, 11%) as a pale yellow solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.20 min, ESI+ found [M+H]=311.

Step 2: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(perfluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide

To a solution of ethyl 6-(1,1,2,2,2-pentafluoroethyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (0.031 g, 0.10 mmol) dissolved in methanol (1 mL) was added 1M aqueous sodium hydroxide (0.15 mL). The reaction mixture was stirred for 1 h at 0° C., then concentrated to dryness in vacuo. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.025 g, 0.1 mmol), N,N-diisopropylethylamine (0.057 mL, 0.33 mmol), and (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.071 g, 0.13 mmol). The reaction mixture was stirred for 16 h at RT, then was purified directly by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1, 2,4]triazolo[4,3-a]pyridine-3-carboxamide (0.015 g, 30%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J=7.8 Hz, 1H), 8.90-8.79 (m, 1H), 7.93 (d, J=9.8 Hz, 1H), 7.57-7.49 (m, 1H), 7.41-7.23 (m, 3H), 4.97 (dt, J=11.4, 7.8 Hz, 1H), 4.62 (dd, J=11.5, 9.9 Hz, 1H), 4.52 (dd, J=9.9, 7.8 Hz, 1H), 3.35 (s, 3H). LC-MS R_(T)=4.81 min, m/z=457.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.81 min, ESI+ found [M+H]=457.1

Example 115 Method G7

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-1H-indazole-3-carboxamide

To a solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.030 g, 0.13 mmol) in N,N-dimethylformamide (2 mL) was added 5-(trifluoromethyl)-1H-indazole-3-carboxylic acid (0.036 g, 0.16 mmol, 1.2 equiv, N,N-diisopropylethylamine (0.046 mL, 0.26 mmol, 2 equiv), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.078 g, 0.14 mmol, 1.1 equiv). The reaction mixture was stirred overnight at RT, then was purified directly by preparative RP-HPLC (20 to 70% acetonitrile in water+0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-1H-indazole-3-carboxamide (0.036 mg, 67%) as a light brown solid: ¹H NMR (400 MHz, DMSO-d6) δ 14.15 (s, 1H), 8.62 (d, J=8.0 Hz, 1H), 8.55-8.28 (m, 1H), 7.91-7.83 (m, 1H), 7.75-7.68 (m, 1H), 7.56-7.49 (m, 1H), 7.40-7.22 (m, 3H), 4.96 (dt, J=11.6, 7.8 Hz, 1H), 4.66 (dd, J=11.6, 9.9 Hz, 1H), 4.48 (dd, J=9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LC-MS R_(T)=5.43 min, m/z=405.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.43 min, ESI+ found [M+H]=405.1

Example 116 Method G13

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(perfluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide

Step 1: ethyl 6-(1,1,2,2,2-pentafluoroethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.100 g, 0.37 mmol) in N,N-dimethylformamide (2 mL) was added (1,1,2,2,2-Pentafluoroethyl)(1,10-phenanthroline-κN1, κN10)copper (0.201 g, 0.56 mmol, 1.5 equiv). The reaction mixture was heated to 90° C. for 24 h, then was diluted with isopropyl acetate (25 mL) and water (25 mL). The layers were separated, and the aqueous was extracted two more times with isopropyl acetate (2×25 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 6-(1,1,2,2,2-pentafluoroethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.055 mg, 0.18 mmol, 48%) as an off white solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.24 min, ESI+ found [M+H]=310

Step 2: ethyl 6-(1,1,2,2,2-pentafluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

To a solution of ethyl 6-(1,1,2,2,2-pentafluoroethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.055 g, 0.18 mmol) in methanol (2 mL) was added palladium hydroxide (10 wt %, 0.037 g, 0.027 mmol, 0.15 equiv). The reaction mixture stirred for 16 h at RT under a balloon of hydrogen. The reaction mixture was then filtered through Celite and concentrated to dryness in vacuo affording ethyl 6-(1,1,2,2,2-pentafluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.055 g, 98%) as a white solid which was used without further purification.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.14 min, ESI+ found [M+H]=314

Step 3: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(perfluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide

To a solution of ethyl 6-(1,1,2,2,2-pentafluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.055 g, 0.18 mmol) dissolved in methanol (1 mL) was added 1M aqueous sodium hydroxide (0.200 mL). The reaction mixture was stirred for 1 h at RT, then concentrated to dryness in vacuo. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.030 g, 0.13 mmol), N,N-diisopropylethylamine (0.069 mL, 0.39 mmol), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.086 g, 0.16 mmol). The reaction mixture was stirred for 16 h at RT, then was purified directly by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(perfluoroethyl)-5,6, 7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (0.049 g, 81%) as a white solid:

¹H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J=8.1, 1.3 Hz, 1H), 7.50 (ddd, J=7.3, 1.9, 0.9 Hz, 1H), 7.38-7.26 (m, 2H), 7.26-7.20 (m, 1H), 4.89-4.78 (m, 1H), 4.72-4.59 (m, 2H), 4.40 (ddd, J=9.8, 7.6, 3.3 Hz, 1H), 4.13-4.02 (m, 1H), 3.32 (s, 3H), 3.17-3.08 (m, 1H), 3.00-2.88 (m, 1H), 2.26-2.15 (m, 1H), 2.01-1.83 (m, 1H). LC-MS R_(T)=5.00 min, m/z=460.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.00 min, ESI+ found [M+H]=460.1

Example 117 Method G8

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

Step 1: methyl 5-bromo-1-(2,4,6-trimethylphenyl)sulfonyl-pyrazolo[3,4-b]pyridine-3-carboxylate

To a suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (0.500 g, 1.95 mmol) in tetrahydrofuran (10 mL) was added triethylamine (0.544 mL, 3.93 mmol, 2 equiv), 2-mesitylenesulfonyl chloride (0.475 g, 2.15 mmol, 1.1 equiv), and 4-(dimethylamino)pyridine 0.024 mg, 0.20 mmol, 0.1 equiv). The reaction mixture was stirred at RT for 16 h, then was concentrated to dryness in vacuo affording methyl 5-bromo-1-(2,4,6-trimethylphenyl)sulfonyl-pyrazolo[3,4-b]pyridine-3-carboxylate (0.855 g, 99%) as an orange solid which was used in the next step without further purification.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.77 min, ESI+ found [M+H]=440

Step 2: methyl 5-(1,1,2,2,2-pentafluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

To a solution of methyl 5-bromo-1-(2,4,6-trimethylphenyl)sulfonyl-pyrazolo[3,4-b]pyridine-3-carboxylate (0.855 g, 1.95 mmol) in 1-methyl-2-pyrrolidinone was added (1,1,2,2,2-pentafluoroethyl)(1,10-phenanthroline-κN1, κN10)copper (0.990 g, 2.73 mmol, 1.4 equiv). The reaction mixture was heated to 80° C. for 24 h, then was diluted with water (100 mL) and extracted with isopropyl acetate (3×50 mL). The combined organics were washed with water (75 mL) and brine (75 mL), dried over sodium sulfate, and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 25% isopropyl acetate in heptane) affording methyl 5-(1,1,2,2,2-pentafluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (0.020 g, 3%) as a pale yellow oil.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.24 min, ESI+ found [M+H]=296

Step 3: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

To a solution of methyl 5-(1,1,2,2,2-pentafluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (0.020 g, 0.07 mmol) dissolved in methanol (1 mL) was added 1M aqueous sodium hydroxide (0.135 mL). The reaction mixture was stirred at 70° C. for 16 h, then concentrated to dryness in vacuo. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.030 g, 0.13 mmol), N,N-diisopropylethylamine (0.069 mL, 0.39 mmol), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.086 g, 0.16 mmol). The reaction mixture was stirred for 16 h at RT, then was purified directly by preparative RP-HPLC (20-70% acetonitrile in water+0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (0.005 g, 17%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 14.87 (s, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.82 (d, J=8.0 Hz, 1H), 8.68 (d, J=2.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.38-7.22 (m, 3H), 4.95 (dt, J=11.6, 7.9 Hz, 1H), 4.69 (dd, J=11.6, 9.9 Hz, 1H), 4.47 (dd, J=9.9, 7.7 Hz, 1H), 3.33 (s, 3H). LC-MS R_(T)=5.43 min, m/z=456.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.43 min, ESI+ found [M+H]=456.1

Example 118 Method G9

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4′ H,6′H-spiro[cyclopentane-1,5′-pyrrolo[1,2-c][1,2,3]triazole]-3′-carboxamide

Step 1: ethyl 2-(8-azaspiro[4.4]nonan-7-ylidene)-2-nitro-acetate

To a solution of 8-azaspiro[4.4]nonan-7-one (1.39 g, 10 mmol) in dichloromethane (50 mL) was added potassium carbonate (4.15 g, 30 mmol, 3 equiv) and trimethyloxonium tetrafluoroborate (2.96 g, 20 mmol, 2 equiv). The reaction mixture was stirred for 16 h at RT, then was diluted with water (100 mL) and the layers separated. The aqueous was extracted two more times with dichloromethane (2×75 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, and concentrated to dryness in vacuo. The residue was resuspended in ethyl nitroacetate (4.45 mL, 40 mmol, 4 equiv) and heated to 70° C. for 7 h. After cooling to rt, the mixture was purified directly by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) affording ethyl 2-(8-azaspiro[4.4]nonan-7-ylidene)-2-nitro-acetate (1.09 g, 43%) as a yellow oil.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.25 min, ESI+ found [M+H]=255

Step 2: ethyl spiro[4,6-dihydropyrrolo[1,2-c]triazole-5,1′-cyclopentane]-3-carboxylate

To a solution of ethyl (2E)-2-(8-azaspiro[4.4]nonan-7-ylidene)-2-nitro-acetate (1.09 g, 4.29 mmol) in acetic acid (13.4 mL) cooled to 0° C. was added zinc dust (1.68 g, 25.7 mmol, 6 equiv). The reaction mixture was warmed to RT and stirred for 1 h. After this time, the mixture was filtered through Celite, the filtrate was cooled to 0° C., and to it was added trifluoroacetic acid (1.13 mL, 15.0 mmol, 3.5 equiv) followed by tert-butyl nitrite (1.68 mL, 14.1 mmol, 3.3 equiv). The reaction mixture was warmed to RT and stirred for 2 h. After this time, water (13.4 mL) was added, and then the entire mixture was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 70% isopropyl acetate in heptane) affording ethyl spiro[4,6-dihydropyrrolo[1,2-c]triazole-5,1′-cyclopentane]-3-carboxylate (0.410 g, 47%).

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.18 min, ESI+ found [M+H]=236

Step 3: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4′ H,6′H-spiro[cyclopentane-1,5′-pyrrolo[1,2-c][1,2,3]triazole]-3′-carboxamide

To a solution of ethyl spiro[4,6-dihydropyrrolo[1,2-c]triazole-5,1′-cyclopentane]-3-carboxylate (0.105 g, 0.45 mmol) dissolved in methanol (1 mL) was added 1M aqueous sodium hydroxide (0.893 mL). The reaction mixture was stirred at 50° C. for 1 h, then concentrated to dryness in vacuo. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.035 g, 0.15 mmol), N,N-diisopropylethylamine (0.080 mL, 0.46 mmol), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.100 g, 0.18 mmol). The reaction mixture was stirred for 16 h at RT, then was purified directly by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (0.039 g, 66%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=8.0 Hz, 1H), 7.53-7.46 (m, 1H), 7.38-7.19 (m, 3H), 4.84 (dt, J=11.6, 7.9 Hz, 1H), 4.61 (dd, J=11.6, 9.9 Hz, 1H), 4.40 (dd, J=9.9, 7.7 Hz, 1H), 4.25 (d, J=0.9 Hz, 2H), 3.31 (s, 3H), 2.88 (s, 2H), 1.80-1.62 (m, 8H). LC-MS R_(T)=4.82 min, m/z=382.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.82 min, ESI+ found [M+H]=382.2

(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4′H,6′H-spiro[cyclopentane-1,5′-pyrrolo[1,2-c][1,2,3]triazole]-3′-carboxamide

(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4′H,6′H-spiro[cyclopentane-1,5′-pyrrolo[1,2-c][1,2,3]triazole]-3′-carboxamide was prepared from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one according to Method G9. Yield of final step: 0.019 g, 30%: ¹H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=7.9 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 6.32 (d, J=2.0 Hz, 1H), 4.43-4.27 (m, 2H), 4.25 (d, J=1.0 Hz, 2H), 4.19 (ddd, J=14.6, 12.7, 6.6 Hz, 1H), 3.25 (s, 3H), 2.89 (s, 2H), 2.58 (ddd, J=12.9, 8.0, 5.0 Hz, 1H), 2.47-2.35 (m, 1H), 1.81-1.59 (m, 8H). LC-MS R_(T)=3.80 min, m/z=370.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.80 min, ESI+ found [M+H]=370.2

Example 119

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole-3-carboxamide

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole-3-carboxamide was prepared from 4-phenyl-2-pyrrolidinone according to Method G9. Yield of final step: 0.048 g, 78%: ¹H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=8.1 Hz, 1H), 7.53-7.45 (m, 1H), 7.42-7.20 (m, 8H), 4.91-4.81 (m, 2H), 4.63 (ddd, J=11.6, 9.9, 1.5 Hz, 1H), 4.49-4.31 (m, 3H), 3.48-3.38 (m, 1H), 3.32 (s, 3H), 3.00 (dd, J=16.3, 8.4 Hz, 1H). LC-MS R_(T)=4.93 min, m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.93 min, ESI+ found [M+H]=404.1

Example 120

(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4′H,6′H-spiro[cyclopentane-1,5′-pyrrolo[1,2-c][1,2,3]triazole]-3′-carboxamide was prepared according to Method G9.

1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=7.8 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.42-7.32 (m, 4H), 7.32-7.24 (m, 1H), 6.32 (d, J=2.0 Hz, 1H), 4.85 (ddd, J=11.3, 8.1, 3.6 Hz, 1H), 4.50-4.27 (m, 3H), 4.20 (ddd, J=14.6, 12.6, 6.6 Hz, 1H), 3.48-3.38 (m, 1H), 3.25 (d, J=1.6 Hz, 3H), 3.01 (dd, J=16.4, 8.3 Hz, 1H), 2.66-2.54 (m, 1H), 2.48-2.37 (m, 1H).

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.97 min, ESI+ found [M+H]=392.2

Example 121

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole-3-carboxamide

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5, 6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole-3-carboxamide was prepared from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one and 4-phenyl-2-pyrrolidinone according to Method G9. Yield of final step: 0.013 g, 19%: ¹H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=7.8 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.42-7.32 (m, 4H), 7.32-7.24 (m, 1H), 6.32 (d, J=2.0 Hz, 1H), 4.85 (ddd, J=11.3, 8.1, 3.6 Hz, 1H), 4.50-4.27 (m, 3H), 4.20 (ddd, J=14.6, 12.6, 6.6 Hz, 1H), 3.48-3.38 (m, 1H), 3.25 (d, J=1.6 Hz, 3H), 3.01 (dd, J=16.4, 8.3 Hz, 1H), 2.66-2.54 (m, 1H), 2.48-2.37 (m, 1H). LC-MS R_(T)=3.97 min, m/z=392.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.97 min, ESI+ found [M+H]=392.2.

Example 122 Method G10

(S)-1-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: 6-chloro-1-isopropyl-pyrazolo[3,4-d]pyrimidine

To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.417 g, 2.70 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added potassium carbonate (0.745 g, 5.40 mmol, 2 equiv) and 2-iodopropane (0.540 mL, 5.4 mmol, 2 equiv). The reaction mixture was stirred for 3 h at 60° C., then was diluted with dichloromethane, filtered through Celite, and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) affording 6-chloro-1-isopropyl-pyrazolo[3,4-d]pyrimidine (0.240 g, 45%) as a white solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.11 min, ESI+ found [M+H]=197.

Step 2: 1-isopropylpyrazolo[3,4-d]pyrimidine-6-carbonitrile

To a solution of sodium cyanide (0.071 g, 1.46 mmol, 1.2 equiv) in water (1.5 mL) was added 1,4-diazabicyclo[2.2.2]octane (0.025 mL, 0.24 mmol, 0.20000 equiv), followed by a solution of 6-chloro-1-isopropyl-pyrazolo[3,4-d]pyrimidine (0.240 g, 1.2205 mmol, 1 equiv) in dimethyl sulfoxide (1.5 mL). The reaction mixture stirred for 16 h at RT, then was diluted with water (50 mL) and extracted with isopropyl acetate (3×50 mL). The combined organics were washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% isopropyl acetate in heptane) affording 1-isopropylpyrazolo[3,4-d]pyrimidine-6-carbonitrile (0.036 g, 16%) as an orange solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.14 min, ESI+ found [M+H]=188.

Step 3: (S)-1-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

To a suspension of 1-isopropylpyrazolo[3,4-d]pyrimidine-6-carbonitrile (0.036 g, 0.19 mmol) in water (0.5 mL) was added 1M aqueous sodium hydroxide (0.577 mL). The reaction mixture was stirred at 50° C. for 2 h, then concentrated to dryness in vacuo. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (0.035 g, 0.15 mmol), N,N-diisopropylethylamine (0.080 mL, 0.46 mmol), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.100 g, 0.18 mmol). The reaction mixture was stirred for 16 h at RT, then was purified directly by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) affording (S)-1-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (0.028 g, 48%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.13 (d, J=7.8 Hz, 1H), 8.51 (s, 1H), 7.58-7.49 (m, 1H), 7.39-7.24 (m, 3H), 5.27 (p, J=6.7 Hz, 1H), 4.92 (dt, J=11.1, 7.9 Hz, 1H), 4.65-4.49 (m, 2H), 3.35 (s, 3H), 1.53 (dd, J=6.7, 0.8 Hz, 6H). LC-MS R_(T)=4.44 min, m/z=381.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.44 min, ESI+ found [M+H]=381.1

Example 123

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide was prepared from 5-phenylmorpholin-3-one and [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride according to Method G11. Yield of final step: 0.025 g, 39%: ¹H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J=8.0 Hz, 1H), 7.54-7.46 (m, 1H), 7.43-7.16 (m, 8H), 5.65 (t, J=4.5 Hz, 1H), 5.13 (d, J=15.7 Hz, 1H), 5.04-4.96 (m, 1H), 4.81 (dt, J=11.5, 7.9 Hz, 1H), 4.59 (dd, J=11.6, 9.9 Hz, 1H), 4.44-4.31 (m, 2H), 3.30 (s, 3H). LC-MS R_(T)=4.57 min, m/z=420.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.57 min, ESI+ found [M+H]=420.1

Example 124 Method G11

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: 1-amino-5-phenyl-pyrrolidin-2-one

To a solution of 5-phenylpyrrolidin-2-one (0.200 g, 1.24 mmol) in 1,2-dimethoxyethane (8 mL) was added sodium hydride (60% suspension in mineral oil, 0.099 g, 2.48 mmol, 2 equiv). The reaction mixture was stirred for 30 mins at RT, then was cooled to 0° C. To the cooled mixture was added a solution of O-mesitylenesulfonylhydroxylamine (0.610 g, 2.83 mmol, 2.3 equiv) in 1,2-dimethoxyethane (5 mL). The resulting mixture was warmed to RT and stirred for 16 h. The reaction was quenched with methanol (0.1 mL) and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 7.5% methanol in isopropyl acetate) affording 1-amino-5-phenyl-pyrrolidin-2-one (0.195 g, 89%) as a white solid.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.11 min, ESI+ found [M+H]=177.

Step 2: ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a suspension of 1-amino-5-phenyl-pyrrolidin-2-one (0.150 g, 0.85 mmol) in toluene (1.5 mL) was added acetic acid (0.15 mL, 2.6 mmol, 3 equiv) followed by ethyl 2-amino-2-thioxo-acetate (0.125 g, 0.94 mmol, 1.1 equiv). The reaction mixture was heated to 90° C. and stirred for 16 h. The mixture was loaded directly onto silica gel and purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.024 g, 11%) as a colorless oil.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.09 min, ESI+ found [M+H]=258.

Step 3: N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

To a solution of ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (0.024 g, 0.09 mmol) in tetrahydrofuran (0.5 mL) was added 1M aqueous sodium hydroxide (0.187 mL). The reaction mixture was stirred at 50° C. for 1 h, then concentrated to dryness in vacuo. The residue was resuspended in N,N-dimethylformamide (2 mL), and to it was added (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.030 g, 0.17 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.109 g, 0.20 mmol). The reaction mixture was stirred for 16 h at RT, then was purified directly by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.023 g, 34%) as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J=7.5 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.44-7.32 (m, 3H), 7.27-7.20 (m, 2H), 6.33 (dd, J=2.0, 1.0 Hz, 1H), 5.57 (dd, J=8.2, 5.9 Hz, 1H), 4.41-4.24 (m, 2H), 4.24-4.12 (m, 1H), 3.24 (d, J=1.1 Hz, 3H), 3.22-3.06 (m, 2H), 3.05-2.94 (m, 1H), 2.61-2.52 (m, 2H), 2.44-2.30 (m, 1H). LC-MS R_(T)=3.73 min, m/z=392.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.73 min, ESI+ found [M+H]=392.2

Examples 125 and 126 Method G12

(R)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (S)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (1:1)

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide was further purified by chiral SFC (Lux Cellulose-4 column, 50% methanol+0.1% ammonium hydroxide isocratic elution) affording arbitrarily assigned diastereomers (R)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phen yl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.006 g, 9%) and (S)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.006 g, 9%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R,S configuration): SFC R_(T) (Lux Cellulose-4 column, 50% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 1.14 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=7.8 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.44-7.32 (m, 3H), 7.28-7.20 (m, 2H), 6.33 (d, J=2.0 Hz, 1H), 5.57 (dd, J=8.2, 5.9 Hz, 1H), 4.41-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.23-4.13 (m, 1H), 3.24 (s, 3H), 3.21-3.14 (m, 1H), 3.14-3.04 (m, 1H), 3.04-2.93 (m, 1H), 2.63-2.52 (m, 2H), 2.37 (td, J=12.5, 6.6 Hz, 1H). LCMS R_(T)=3.76 min, m/z=392.2 (M+H)⁺.

Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T): 1.84 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=7.7 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.43-7.32 (m, 3H), 7.26-7.21 (m, 2H), 6.33 (d, J=2.0 Hz, 1H), 5.57 (dd, J=8.3, 5.8 Hz, 1H), 4.41-4.24 (m, 2H), 4.24-4.12 (m, 1H), 3.24 (s, 3H), 3.22-3.06 (m, 2H), 3.05-2.94 (m, 1H), 2.61-2.52 (m, 2H), 2.42-2.31 (m, 1H). LCMS R_(T)=3.76 min, m/z=392.2 (M+H)⁺.

Example 127 Method C1

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(2,2,2 trifluoroethyl)pyrazolo[4,3-c]pyridine-6-carboxamide

Step 1: 6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

A solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (1.0 g, 5.05 mmol) in N,N-dimethylformamide (9.2 mL) was cooled to 0° C. and sodium hydride (60 mass % in oil, 0.460 g, 11.5 mmol) was added. After 5 min, 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.0 g, 12.9 mmol) was added. The reaction stirred at 0° C. for 10 min and then was warmed to RT and stirred for an additional 18 h. The reaction mixture was sealed with a yellow cap and heated at 60° C. for 1 h. After cooling to RT, the reaction was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate (3×100 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, concentrated to dryness in vacuo, and the residue was purified by flash column chromatography (silica gel, 0% to 50% isopropyl acetate-heptane) to give 6-bromo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine (0.925 g, 3.30 mmol, 65% Yield): ¹H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.47 (s, 1H), 8.20 (s, 1H), 5.47 (q, J=8.8 Hz, 2H). LRMS R_(T)=1.25 min, m/z=281 (M+H)⁺.

Step 2: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(2,2,2 trifluoroethyl)pyrazolo[4,3-c]pyridine-6-carboxamide

Palladium(II) acetate (3.1 mg, 0.0134 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.9 mg, 0.0134 mmol), 6-bromo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine (75 mg, 0.268 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (77.2 mg, 0.402 mmol) were added to a screw-cap vial (not dried). A septum was put on the vial and secured with electrical tape. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (0.53 mL), and triethylamine (0.110 mL, 0.803 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial, with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 16 h. (NOTE: no solvent remained after heating for 16 h). The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 60% isopropyl acetate in heptane) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-c]pyridine-6-carboxamide (102.6 mg, 0.242 mmol, 90% Yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (d, J=1.2 Hz, 1H), 9.06 (d, J=8.0 Hz, 1H), 8.59 (d, J=0.8 Hz, 1H), 8.52 (bs, 1H), 7.57-7.47 (m, 1H), 7.40-7.24 (m, 3H), 5.75-5.60 (m, 2H), 4.93 (dt, J=10.8, 8.0 Hz, 1H), 4.62-4.48 (m, 2H), 3.35 (s, 3H). LRMS R_(T)=5.04 min, m/z=420.1 (M+H)⁺.

Prep HPLC Information: Column: Phenomenex Gemini-NX C18 5 um, 110 A (50×30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A)/Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 900 psi

Flow Rate: 60 mL/min

Column Temperature: 25° C. Wavelength: 220 nm Example 128 Method C2

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

Step 1: 6-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridine

A suspension of sodium hydride (60 mass % in oil, 0.480 g, 12.0 mmol) in N,N-dimethylformamide (9.2 mL) was cooled to 0° C. and 6-bromo-1H-pyrazolo[4,3-c]pyridine (1.0 g, 5.05 mmol) was added. After 5 min, 3-bromotetrahydrofuran (1.80 g, 11.9 mmol) was added. The reaction stirred at 0° C. for 10 min, warmed to RT and stirred for an additional 18 h. Additional sodium hydride (60 mass % in oil, 0.230 g, 5.75 mmol) and 3-bromotetrahydrofuran (0.90 g, 5.96 mmol) was added. The reaction was sealed with a yellow cap and heated at 60° C. for 4 h. After cooling to RT, the reaction was diluted with water and isopropyl acetate. The aqueous layer was extracted with isopropyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, concentrated to dryness in vacuo, and the residue was purified by flash column chromatography (silica gel, 0% to 50% isopropyl acetate in heptane) to give 6-bromo-1-tetrahydrofuran-3-yl-pyrazolo[4,3-c]pyridine (0.579 g, 2.16 mmol, 43% Yield):

¹H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 5.63-5.37 (m, 1H), 4.21-3.98 (m, 2H), 3.98-3.72 (m, 2H), 2.65-2.36 (m, 1H), 2.36-2.19 (m, 1H). LRMS R_(T)=1.03 min, m/z=269 (M+H)⁺.

Step 2: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

Palladium(II) acetate (2.6 mg, 0.0112 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.6 mg, 0.0112 mmol), 6-bromo-1-tetrahydrofuran-3-yl-pyrazolo[4,3-c]pyridine (60 mg, 0.224 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (64.5 mg, 0.336 mmol) were added to a screw-cap vial (not dried). A septum was put on the vial and secured with electrical tape. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (0.45 mL), and then triethylamine (0.095 mL, 0.671 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial, with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 17 h. (NOTE: no solvent remained after heating for 17 h). The crude residue was dissolved in isopropyl acetate, filtered through Celite and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 75% isopropyl acetate in heptane) to give N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide (55 mg, 60% Yield): ¹H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=0.8 Hz, 1H), 9.02 (d, J=8.0 Hz, 1H), 8.47-8.46 (m, 1H), 8.40-8.36 (m, 1H), 7.57-7.47 (m, 1H), 7.39-7.24 (m, 3H), 5.73-5.66 (m, 1H), 4.96-4.89 (m, 1H), 4.61-4.50 (m, 2H), 4.14-4.01 (m, 2H), 3.96-3.82 (m, 2H), 3.35 (s, 3H), 2.51-2.39 (m, 1H), 2.34-2.19 (m, 1H). LRMS R_(T)=4.49 min, m/z=408.2 (M+H)⁺.

Prep HPLC Information: Column: Phenomenex Gemini-NX C18 5 um, 110 A (50×30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A)/Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 900 psi

Flow Rate: 60 mL/min

Column Temperature: 25° C. Wavelength: 230 nm Examples 129 and 130 Method C3

1-benzyl-N-((1S,4S,7R)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1, 2,4-triazole-3-carboxamide and 1-benzyl-N-((1R,4S,7S)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1, 2,4-triazole-3-carboxamide

Step 1: (S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhexanoic acid

((Benzyloxy)carbonyl)-L-lysine (150 g, 535 mmol) was dissolved in water (1.5 L), and the solution was warmed to 60° C. and adjusted to pH=9.5 with 4M NaOH, disodium pentacyano(nitroso)irondiuide (168 g, 642 mmol) was added slowly with vigorous stirring over 10 min. The reaction mixture was stirred at 60° C. for and maintained pH=9.5 with 4N NaOH for 12 h. The reaction mixture was flittered through a bed of Celite, the filtrate was cautiously acidified with hydrochloric acid to pH=1, and then extracted with ethyl acetate (3×1000 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo to afford (S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhexanoic acid (260 g, crude) as a brown oil, use without further purification in the next step.

Step 2: benzyl (S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhexanoate

A mixture of (S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhexanoic acid (130 g, 462 mmol,), cesium carbonate (75 g, 231 mmol), bromomethylbenzene (79. g, 462 mmol) in N,N-dimethylformamide (1 L) and the mixture was stirred at 10° C. for 18 h under nitrogen atmosphere. The reaction mixture was filtered, the filtrate was diluted with water (5 L), the aqueous phase was extracted with ethyl acetate (3×1 L). The combined organic was washed with brine (200 mL), dried with anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 50:1 to 0:1 ethyl acetate in petroleum ether) affording benzyl (S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhexanoate (222 g, 65%) as a white oil, use without further purification in the next step: HPLC R_(T)=3.16 min

Step 3: (S)-2-amino-6-hydroxyhexanoic acid

To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhexanoate (222 g, 598 mmol) in methanol (1 L) was added 10% Pd/C (20 g) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 50° C. for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo to give (S)-2-amino-6-hydroxyhexanoic acid (85 g, 577 mmol, 97% yield) as a white solid, used use without further purification in the next step: TLC (Petroleum ether/Ethyl acetate=2/1, Rf=0.45)

Step 4: (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxyhexanoic acid

To a mixture of (S)-2-amino-6-hydroxyhexanoic acid (50 g, 340 mmol), ethyl 1,3-dioxoisoindoline-2-carboxylate (74 g, 340 mmol) was added sodium carbonate (36 g, 340 mmol) in water (500 mL) was stirred at 10° C. for 2. The reaction mixture was adjust pH=1 and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was washed with 2-methoxy-2-methylpropane (300 mL) and dried to afford (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxyhexanoic acid (47 g, 50%) as a white solid, use without further purification in the next step: HPLC R_(T)=1.83 min

Step 5: (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxy-N-methylhexanamide

A mixture of (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxyhexanoic acid (32 g, 115 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (33 g, 173 mmol), benzotriazol-1-ol (16 g, 115 mmol) and methanamine (2 M solution in tetrahydrofuran, 144 mL, 287.5 mmol) in tetrahydrofuran (320 mL) was degassed and purged with nitrogen, and the reaction mixture was stirred at 10° C. for 2 h under a nitrogen atmosphere. To the reaction mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 200:1, 50:1 methanol in dichloromethane) to afford (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxy-N-methylhexanamide (16.5 g, 49% yield), used as is in the next step

Step 6: 2-((3S)-7-hydroxy-1-methyl-2-oxoazepan-3-yl)isoindoline-1,3-dione

To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxy-N-methylhexanamide (13.8 g, 48 mmol) in dimethylsulfoxide (84 mL) were added triethylamine (24 g, 238 mmol, 33 mL) and sulfur trioxide pyridine complex (38 g, 238 mmol) at 0° C. under an argon atmosphere and the mixture was stirred at 10-20° C. for 2.5 h. The reaction mixture was quenched with water and treated with 1N HCl, and then extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness in vacuo to afford 2-((3S)-7-hydroxy-1-methyl-2-oxoazepan-3-yl)isoindoline-1,3-dione (21.2 g, crude) as off-white oil, which was used in the next step without further purification: TLC (dichloromethane/Methanol=10/1, Rf=0.43)

Step 7: (S)-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-azepin-3-yl)isoindoline-1,3-dione

A solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-6-hydroxy-N-methylhexanamide (21.2 g, 73 mmol) and p-toluenesulfonic acid monohydrate (839 mg, 4.4 mmol) in toluene (200 mL) was stirred under reflux for 1.5 h. After allowing to cool to RT, the reaction mixture was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo. The residue was washed with ethyl acetate (10 mL) and dried to afford (S)-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-azepin-3-yl)isoindoline-1,3-dione (4.6 g, 23%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.88 (dd, J=5.52, 3.01 Hz, 2H), 7.71-7.77 (m, 2H), 5.96 (dd, J=9.03, 1.51 Hz, 1H), 5.35-5.45 (m, 1H), 5.04 (dd, J=10.79, 3.26 Hz, 1H), 3.10 (s, 3H), 2.46-2.57 (m, 1H), 2.23-2.40 (m, 2H), 1.61 (s, 1H).

Step 1: 2-((4S)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)isoindoline-1,3-dione

A solution of sodium chlorodifluoroacetate (1.42 g, 9.25 mmol) in diglyme (5.9 mL) was added dropwise to a refluxing solution of 2-[(3S)-1-methyl-2-oxo-4,5-dihydro-3H-azepin-3-yl]isoindoline-1,3-dione (0.250 g, 0.925 mmol) in diglyme (10 mL) over 25 minutes. After addition, the reaction was allowed to stir for an additional 10 minutes at reflux. After cooling to RT, the reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash column chromatography (silica gel, 0% to 70% isopropyl acetate in heptane) affording 2-[(4S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[5.1.0]octan-4-yl]isoindoline-1,3-dione (0.270 g, 0.843 mmol, 91% yield) as an inseparable ˜6.8:1 mixture of diastereomers: ¹H NMR (400 MHz, Chloroform-d) 6 (major isomer) 7.90-7.81 (m, 2H), 7.75-7.70 (m, 2H), 5.44 (dd, J=11.6, 8.0 Hz, 1H), 3.66-3.30 (m, 1H), 3.26-3.11 (m, 1H), 3.02 (s, 3H), 2.25-2.15 (m, 1H), 2.04-1.90 (m, 2H), 1.85-1.72 (m, 1H). LRMS R_(T)=1.29 min, m/z=321 (M+H)⁺.

Step 2: 1-benzyl-N-((1S,4S,7R)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1, 2,4-triazole-3-carboxamide and 1-benzyl-N-((1R,4S,7S)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1, 2,4-triazole-3-carboxamide

Hydrazine (0.087 mL, 2.72 mmol) was added to a solution of 2-[(4S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[5.1.0]octan-4-yl]isoindoline-1,3-dione and (˜6.8:1 dr, 0.290 g, 0.905 mmol) in ethanol (9.1 mL). The reaction was heated at 80° C. for 2 h. After cooling to RT, the reaction was filtered through a short plug of Celite using ethanol. The filtrate was concentrated to dryness in vacuo to afford (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo[5.1.0]octan-5-one (88.9 mg, 0.467 mmol, 51.6% Yield). The crude residue was used in the next step without further purification.

(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.138 g, 0.254 mmol) was added to a solution of (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo[5.1.0]octan-5-one (44 mg, 0.231 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (58 mg, 0.289 mmol), and N,N-diisopropylethylamine (0.120 mL, 0.694 mmol), in N,N-dimethylformamide (2.3 mL). The reaction was allowed to stir at RT for 18 h before being concentrated to dryness in vacuo. The crude residue was purified by preparative reverse phase HPLC affording arbitrarily assigned 1-benzyl-N-((1S,4S,7R)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1,2, 4-triazole-3-carboxamide (56.7 mg, 0.151 mmol, 65% Yield) and 1-benzyl-N-((1R,4S,7S)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1,2, 4-triazole-3-carboxamide (5.7 mg, 6.6%): 1-benzyl-N-((1S,4S,7R)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1,2, 4-triazole-3-carboxamide (arbitrarily assigned): ¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.19 (m, 2H), 7.45-7.20 (m, 5H), 5.49 (s, 2H), 5.00 (dt, J=10.8, 7.2 Hz, 1H), 3.72-3.49 (m, 1H), 2.90 (s, 3H), 2.43-1.96 (m, 4H), 1.61 (m, 1H), 1.27 (m, 1H). LRMS R_(T)=4.18 min, m/z=376.1 (M+H)⁺.

Prep HPLC Information: Column: Phenomenex Gemini-NX C18 5 um, 110 A (50×30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A)/Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 800 psi

Flow Rate: 60 mL/min

Column Temperature: 25° C. Wavelength: 210 nm

and 1-benzyl-N-((1R,4S,7S)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1,2, 4-triazole-3-carboxamide (arbitrarily assigned): ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.58 (d, J=4.4 Hz, 1H), 7.43-7.27 (m, 5H), 5.48 (s, 2H), 4.43-4.33 (m, 1H), 3.27-3.14 (m, 1H), 2.80 (s, 3H), 2.55-2.43 (m, 1H), 2.10-2.00 (m, 3H), 1.30-1.10 (m, 1H). LRMS R_(T)=3.90 min, m/z=376.1 (M+H)⁺.

Prep HPLC Information: Column: Phenomenex Gemini-NX C18 5 um, 110 A (50×30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A)/Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 800 psi

Flow Rate: 60 mL/min

Column Temperature: 25° C. Wavelength: 210 nm Example 131 and 132 Method C3 & C4

Ethyl(1S,4S,7S,8R)-4-(1-benzyl-1H-1,2,4-triazole-3-1H-triazcarboxamido)-2-methyl-3-oxo-2-aza bicyclo[5.1.0]octane-8-carboxylate and ethyl (1R,4S,7R,8S)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate

Step 1: ethyl (4S)-4-(1,3-dioxoisoindolin-2-yl)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate

A solution of ethyl diazoacetate (15 mass % in toluene, 1.3 mL, 1.5 mmol) in dichloromethane (3 mL) was added dropwise to a solution of the 2-[(3S)-1-methyl-2-oxo-4,5-dihydro-3H-azepin-3-yl]isoindoline-1,3-dione (0.20 g, 0.74 mmol) and rhodium(II) acetate (6.9 mg, 0.030 mmol) in dichloromethane (5.2 mL), over a period of 4 h. After, the reaction was allowed to stir for an additional 12 h. The reaction was then filtered through Celite using isopropyl acetate. The filtrate was concentrated to dryness in vacuo and the residue was purified by flash column chromatography (silica gel, 0% to 70% isopropyl acetate in heptane) to give ethyl (4S)-4-(1,3-dioxoisoindolin-2-yl)-6-methyl-5-oxo-6-azabicyclo[5.1.0]octane-8-carboxylate (0.145 g, 0.407 mmol, 55% Yield). LRMS R_(T)=1.28 min, m/z=357 (M+H)⁺.

Step 2: ethyl (1S,4S,7S,8R)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate and ethyl (1R,4S,7R,8S)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate

Hydrazine (0.040 mL, 1.18 mmol) was added to a solution of ethyl (4S)-4-(1,3-dioxoisoindolin-2-yl)-6-methyl-5-oxo-6-azabicyclo[5.1.0]octane-8-carboxylate (0.140 g, 0.393 mmol) in ethanol (3.9 mL). The reaction was heated at 80° C. for 2 h. After cooling to RT, the reaction was filtered through a short plug of Celite using ethanol. The filtrate was concentrated to dryness in vacuo and the residue was submitted to the next step without further purification.

(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.235 g, 0.432 mmol) was added to a solution of the crude residue, 1-benzyl-1,2,4-triazole-3-carboxylic acid (99.8 mg, 0.491 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.18 mmol), in N,N-dimethylformamide (3.9 mL). The reaction was allowed to stir at RT for 18 h before being concentrated to dryness in vacuo. The crude residue was purified by reverse phase preparative HPLC to afford arbitrarily assigned ethyl (1S,4S,7S,8R)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate (23.5 mg, 0.057 mmol, 14.5% Yield) and ethyl (1R,4S,7R,8S)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate (15.6 mg, 0.038 mmol, 9.7% Yield).

Ethyl

(1S,4S,7S,8R)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate: ¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.46-7.19 (m, 4H), 5.49 (s, 2H), 5.07 (dt, J=10.8, 7.2 Hz, 1H), 4.09 (m, 2H), 3.41-3.20 (m, 1H), 2.85 (s, 3H), 2.30-2.12 (m, 2H), 2.01-1.77 (m, 2H), 1.60-1.43 (m, 1H), 1.21 (t, J=7.2 Hz, 3H), 1.15-0.95 (m, 1H). LRMS R_(T)=4.19 min, m/z=412.2 (M+H)⁺.

Prep HPLC Information: Column: Es Industries Pyridyl Amide (150×30 mm) Mobile Phase: Carbon Dioxide (A)/Methanol w/0.1% Ammonium Hydroxide (B) Elution Program Gradient: 5 to 60% B Pressure: 2500 psi

Flow Rate: 100 mL/min

Column Temperature: 40° C. Wavelength: 254 nm Ethyl

(1R,4S,7R,8S)-4-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-2-methyl-3-oxo-2-azabicyclo[5.1.0]octane-8-carboxylate: ¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.19 (d, J=7.6 Hz, 1H), 7.43-7.27 (m, 5H), 5.49 (s, 2H), 4.98 (dt, J=11.2, 7.6 Hz, 1H), 4.16-4.02 (m, 2H), 3.38-3.27 (m, 1H), 2.74 (s, 3H), 2.30-2.22 (m, 1H), 2.16-1.94 (m, 2H), 1.97-1.83 (m, 2H), 1.80-1.74 (m, 1H), 1.68-1.61 (m, 1H), 1.20 (t, J=7.2 Hz, 3H). LRMS R_(T)=4.22 min, m/z=412.2 (M+H)⁺.

Prep HPLC Information: Column: Es Industries Pyridyl Amide (150×30 mm) Mobile Phase: Carbon Dioxide (A)/Methanol w/0.1% Ammonium Hydroxide (B) Elution Program Gradient: 5 to 60% B Pressure: 2500 psi

Flow Rate: 100 mL/min

Column Temperature: 40° C. Wavelength: 254 nm Example 133 Method X1

5-benzyl-N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: 4,5,6,7-tetrahydro-2H-indazol-3-amine

To a solution of 2-oxocyclohexanecarbonitrile (1.71 g, 13.2 mmol) in toluene (23 mL) was added hydrazine (0.485 mL, 14.5 mmol), and the reaction was stirred at 85° C. for 5 h. The reaction mixture was concentrated to dryness in vacuo and the residue was used in the next step without further purification: LCMS R_(T)=0.80 min; m/z=138 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 2: N-(4,5,6,7-tetrahydro-2H-indazol-3-yl)formamide

3-Amino-4,5,6,7-tetrahydro-1H-indazole (1.10 g, 7.7 mmol) and formic acid (4.7 mL, 120 mmol) were mixed together, and the reaction was stirred at 110° C. for 3 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% methanol in dichloromethane) affording N-(4,5,6,7-tetrahydro-2H-indazol-3-yl)formamide (1.143 g, 90% yield) as yellow solid: ¹H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.85 (dd, J=7.9, 3.4 Hz, 1H), 8.51 (d, J=11.0 Hz, 0.55H), 8.08 (d, J=1.7 Hz, 0.35H), 2.54-2.50 (m, 2H), 2.32 (td, J=6.0, 1.9 Hz, 2H), 1.77-1.55 (m, 4H), tautomers were found in NMR; LCMS R_(T)=1.43 min; m/z=166 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 3: N-methyl-4,5,6,7-tetrahydro-2H-indazol-3-amine

To a solution of N-(4,5,6,7-tetrahydro-1H-indazol-3-yl)formamide (2.08 g, 12.6 mmol) in tetrahydrofuran (120 mL) was added lithium aluminum hydride (2 mol/L) in tetrahydrofuran (20.0 mL, 40.0 mmol) at 0° C., and the reaction was stirred at 25° C. for 6 h. Sodium sulfate decahydrate was added, and the mixture was stirred for 18 h. The mixture was filtered through celite, and ethyl acetate was used to rinse the solid. The combined liquid was concentrated to dryness in vacuo to afford N-methyl-4,5,6,7-tetrahydro-1H-indazol-3-amine (2.03 g, 106% yield) as colorless oil used without further purification: ¹H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 4.54 (s, 1H), 2.64 (d, J=5.3 Hz, 3H), 2.45-2.37 (m, 2H), 2.23-2.15 (m, 2H), 1.69-1.56 (m, 4H); LCMS R_(T)=1.30 min; m/z=152 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 4: 4-chloro-N-(1-(4-chlorobutanoyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-N-methylbutanamide

To a solution of N-methyl-4,5,6,7-tetrahydro-1H-indazol-3-amine (2.03 g, 13.4 mmol) and N,N-dimethylpyridin-4-amine (163.7 mg, 1.340 mmol) in dichloromethane (53 mL) and N,N-diisopropylethylamine (5.84 mL) was added 4-chlorobutyryl chloride (3.462 mL, 30.82 mmol) at 0° C., and the reaction was stirred at 0° C. for 30 min then at 25° C. for 8 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in heptane) affording 4-chloro-N-[1-(4-chlorobutanoyl)-4,5,6,7-tetrahydroindazol-3-yl]-N-methyl-butanamide (3.44 g, 71% yield) as oil: LCMS R_(T)=3.11 min; m/z=360 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 5: 4-chloro-N-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-3-yl)butanamide

To a solution of 4-chloro-N-[1-(4-chlorobutanoyl)-4,5,6,7-tetrahydroindazol-3-yl]-N-methyl-butanamide (3.44 g, 9.55 mmol) in ethanol (17 mL) was added sodium hydroxide (1 mol/L) in water (9.5 mL, 9.55 mmol,), and the reaction was stirred at 25° C. for 5 min. The reaction mixture was concentrated to dryness in vacuo and the residue was used without further purification: LCMS R_(T)=2.10 min; m/z=256 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 6: 1-methyl-4,5,8,9,10,11-hexahydro-1H-[1,3]diazepino[1,2-b]indazol-2(3H)-one

To a solution of 4-chloro-N-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-3-yl)butanamide (2.81 g, 11.0 mmol) in N,N-dimethylformamide (49 mL) was added cesium carbonate (5.37 g, 16.5 mmol), and the reaction was stirred at 65° C. for 18 h. The reaction mixture was diluted with ethyl acetate and water, and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in heptane) affording 1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (2.03 g, 63% yield) as a white solid: ¹H NMR (400 MHz, Chloroform-d) δ 4.18 (t, J=6.7 Hz, 2H), 3.24 (s, 3H), 2.65 (dd, J=6.4, 5.6 Hz, 2H), 2.53-2.42 (m, 2H), 2.42-2.25 (m, 4H), 1.90-1.74 (m, 4H); ¹H NMR (400 MHz, DMSO-d6) δ 4.13-4.04 (m, 2H), 2.73 (d, J=0.6 Hz, 3H), 2.56-2.47 (m, 2H), 2.43 (t, J=5.9 Hz, 2H), 2.23-2.07 (m, 4H), 1.79-1.61 (m, 4H); LCMS R_(T)=1.78 min; m/z=220 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 7: 3-iodo-1-methyl-4,5,8,9,10, 11-hexahydro-1H-[1,3]diazepino[1,2-b]indazol-2(3H)-one

To a solution of 1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (1.00 g, 3.42 mmol) in dichloromethane (29 mL) was added N,N,N′,N′-tetramethylethylenediamine (3.09 mL, 20.5 mmol) at −10° C. (1/1 salt/ice bath), followed by fresh iodotrimethylsilane (2.93 mL, 20.5 mmol), and the reaction was stirred in salt/ice bath (at −10˜−15° C.) for 1.5 h. Iodine (2.60 g, 10.3 mmol) was added, and the reaction was stirred in salt/ice bath (at −10˜−15° C.) for 2 h. The crude mixture was diluted with ethyl acetate and sodium sulfite, and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-70% ethyl acetate in dichloromethane) affording 3-iodo-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (0.87 g, 74% yield) as white powder: ¹H NMR (400 MHz, Chloroform-d) δ 4.56 (dd, J=9.3, 7.7 Hz, 1H), 4.23-4.13 (m, 2H), 3.29 (s, 3H), 3.02-2.89 (m, 1H), 2.81-2.70 (m, 1H), 2.69-2.62 (m, 2H), 2.53-2.43 (m, 2H), 1.93-1.69 (m, 4H); ¹H NMR (400 MHz, DMSO-d6) δ 4.56 (dd, J=8.7, 7.8 Hz, 1H), 4.14-4.07 (m, 2H), 3.17 (s, 3H), 2.91-2.77 (m, 1H), 2.62-2.54 (m, 1H), 2.47-2.39 (m, 2H), 1.82-1.63 (m, 4H); LCMS R_(T)=1.25 min; m/z=346 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 8: 3-azido-1-methyl-4,5,8,9,10,11-hexahydro-1H-[1,3]diazepino[1,2-b]indazol-2(3H)-one

To a solution of 3-iodo-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (880 mg, 2.55 mmol) in N,N-dimethylformamide (3.0 mL) was added sodium azide (222 mg, 3.3142 mmol), and the reaction was stirred at 25° C. for 4 h. The crude mixture was diluted with ethyl acetate and water, and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was used without further purification: LCMS R_(T)=2.10 min; m/z=261 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 9: 3-amino-1-methyl-4,5,8,9,10,11-hexahydro-1H-[1,3]diazepino[1,2-b]indazol-2(3H)-one

To a solution of 3-azido-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (330 mg, 1.27 mmol) in tetrahydrofuran (5.3 mL) and water (1.2 mL) was added triphenylphosphine, polymer-bound (7.61 mmol), and the reaction was stirred at 25° C. for 18 h. The crude mixture was filtered through celite, and concentrated to dryness in vacuo. The crude residue was used without further purification: LCMS R_(T)=1.39 min; m/z=235 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 10: 5-benzyl-N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-4H-1,2,4-triazole-3-carboxamide

To a solution of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (32 mg, 0.16 mmol) in N,N-dimethylformamide (0.1 mL) and acetonitrile (0.25 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (62 mg, 0.16 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (25 mg, 0.11 mmol) was added. The reaction was stirred at 25° C. for 18 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording 5-benzyl-N-(1-methyl-2-oxo-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-3-yl)-4H-1,2,4-triazole-3-carboxamide (11 mg, 25% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.7 Hz, 1H), 7.38-7.16 (m, 5H), 4.35-4.08 (m, 3H), 4.06 (s, 2H), 3.19 (s, 3H), 2.65-2.51 (m, 3H), 2.49-2.40 (m, 2H), 2.27-2.16 (m, 1H), 1.87-1.59 (m, 4H); LCMS R_(T)=4.15 min; m/z=420.2 (M+H)⁺.

Example 134 Method X2

1-benzyl-N-(2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydr-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]formamide

To a solution of 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine (1.01 g, 6.35 mmol) in toluene (9.40 mL) was added formic acid (3.8 mL), and the reaction was stirred at 110° C. for 3 h. The crude mixture was concentrated to dryness in vacuo, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in dichloromethane) affording N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]formamide (420 mg, 35% yield) as light brown solid: ¹H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 10.47 (s, 0.70H), 10.10 (s, 0.30H), 8.62 (d, J=11.0 Hz, 0.30H), 8.14 (d, J=1.8 Hz, 0.80H), 6.39 (s, 0.70H), 5.90 (d, J=1.9 Hz, 0.30H), 3.04-2.85 (m, 1H), 2.15-2.00 (m, 1H), 1.96-1.81 (m, 1H); tautomers were found in NMR; LCMS R_(T)=1.18 min; m/z=188 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 2: 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine

To a solution of N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]formamide (787 mg, 4.2 mmol) in tetrahydrofuran (37 mL) was added lithium aluminum hydride (2 mol/L) in tetrahydrofuran (6.38 mL, 12.6 mmol) at 0° C., and the reaction was stirred at 25° C. for 6 h. Sodium sulfate decahydrate was added, and the mixture was stirred for 18 h. The mixture was filtered through celite, and ethyl acetate was used to rinse the solid. The combined liquid was concentrated to dryness in vacuo affording 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (950 mg) as colorless oil used without further purification: ¹H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 5.23 (bs, 1H), 2.81-2.66 (m, 1H), 2.61 (d, J=5.3 Hz, 3H), 1.98-1.87 (m, 1H), 1.77-1.65 (m, 1H); LCMS R_(T)=1.06 min; m/z=174 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 3: 4-chloro-N-(1-(4-chlorobutanoyl)-5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide

To a solution of 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (810 mg, 4.7 mmol) and N,N-dimethylpyridin-4-amine (57 mg, 0.47 mmol) in dichloromethane (19 mL) and N,N-diisopropylethylamine (2.0 mL, 12 mmol) was added 4-chlorobutyryl chloride (1.2 mL, 10 mmol) at 0° C., and the reaction was stirred at 0-25° C. for 18 h. The reaction mixture was concentrated to dryness in vacuo and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in heptane) affording 4-chloro-N-(1-(4-chlorobutanoyl)-5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide (332 mg, 56% yield): ¹H NMR (400 MHz, DMSO-d6) δ 6.86 (s, 1H), 3.74 (t, J=6.5 Hz, 2H), 3.71-3.62 (m, 2H), 3.43-3.33 (m, 2H), 3.23 (t, J=7.3 Hz, 2H), 2.73-2.62 (m, 2H), 2.18-1.87 (m, 6H), CH₃ was not seen in NMR, probably overlapping with HDO peak at 3.30 ppm; LCMS R_(T)=3.07 min; m/z=382 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 4: 4-chloro-N-(5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide

To a solution of 4-chloro-N-[1-(4-chlorobutanoyl)-5-(2,2-difluorocyclopropyl)pyrazol-3-yl]-N-methyl-butanamide (332 mg, 0.87 mmol) in ethanol (1.4 mL) was added sodium hydroxide (1 mol/L) in water (0.87 mL), and the reaction was stirred at 25° C. for 5 min. The reaction mixture was concentrated to dryness in vacuo and the residue was used without further purification: LCMS R_(T)=2.03 min; m/z=278 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 5: 2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-chloro-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (240 mg, 0.86 mmol) in N,N-dimethylformamide (3.9 mL) was added cesium carbonate (422 mg, 1.30 mmol), and the reaction was stirred at 65° C. for 18 h. The crude mixture was diluted with ethyl acetate and citric acid solution (10% aq.), and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-75% ethyl acetate in dichloromethane) affording 2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (118 mg, 56% yield) as colorless oil: ¹H NMR (400 MHz, DMSO-d6) δ 6.18-6.13 (m, 1H), 4.21-4.12 (m, 2H), 3.15 (s, 3H), 2.86 (td, J=12.1, 8.0 Hz, 1H), 2.27-2.17 (m, 4H), 2.03-1.90 (m, 1H), 1.88-1.75 (m, 1H); LCMS R_(T)=1.70 min; m/z=242 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 6: 2-(2,2-difluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (118 mg, 0.49 mmol) in dichloromethane (4.0 mL) cooled to −10° C. in a salt/ice bath was added N,N,N′,N′-tetramethylethylenediamine (0.44 mL, 2.9 mmol), followed by iodotrimethylsilane (0.42 mL, 2.9 mmol), and the reaction was stirred at −10° C. for 1.5 h. Iodine (372 mg, 1.47 mmol) was added, and the reaction was stirred for 2 h. The crude mixture was diluted with ethyl acetate and sodium sulfite solution, and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-70% ethyl acetate in heptane) affording 2-(2,2-difluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (53 mg, 29% yield) as white solid: ¹H NMR (400 MHz, Chloroform-d) δ 5.95 (dd, J=2.4, 1.1 Hz, 1H), 4.62 (ddd, J=9.2, 7.4, 4.7 Hz, 1H), 4.31-4.14 (m, 2H), 3.33 (s, 3H), 3.05-2.89 (m, 1H), 2.84-2.67 (m, 2H), 1.91-1.76 (m, 1H), 1.78-1.65 (m, 1H); LCMS R_(T)=2.15 min; m/z=368 (M+H)⁺

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 7: 6-azido-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 2-(2,2-difluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (53 mg, 0.14 mmol) in N,N-dimethylformamide (0.20 mL) was added sodium azide (11.6 mg, 0.17 mmol), and the reaction was stirred at 25° C. for 2 h. The crude mixture was used without further purification: LCMS R_(T)=2.06 min; m/z=283 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 8: 6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 6-azido-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (41 mg, 0.14 mmol) in tetrahydrofuran (0.5 mL) and water (0.15 mL) was added polymer-bound triphenylphosphine (0.87 mmol), and the reaction was stirred at 25° C. for 18 h. The crude mixture was filtered through celite, and concentrated to dryness in vacuo. The crude material was used without further purification: LCMS R_(T)=1.19 min; m/z=257 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 9: 1-benzyl-N-[2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

To a solution of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (62 mg, 0.29 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (112 mg, 0.29 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min. 6-Amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (37 mg, 0.14 mmol, 37 mg) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording 1-benzyl-N-[2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (36.5 mg, 57%) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.44-7.25 (m, 5H), 6.34-6.23 (m, 1H), 5.48 (s, 2H), 4.36-4.25 (m, 2H), 4.23-4.09 (m, 1H), 3.22 (d, J=2.1 Hz, 3H), 2.99-2.78 (m, 1H), 2.67-2.53 (m, 1H), 2.44-2.31 (m, 1H), 2.02-1.80 (m, 2H); LCMS R_(T)=4.36 min; m/z=442.2 (M+H)⁺.

Example 135 Method X3

Step 1: 1-benzyl-N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-benzyl-1H-1,2,3-triazole-4-carboxylic acid (75 mg, 0.35 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (136 mg, 0.35 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (41 mg, 0.17 mmol) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording 1-benzyl-N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-1H-1,2,3-triazole-4-carboxamide (42 mg, 57% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.49 (d, J=7.7 Hz, 1H), 7.46-7.25 (m, 5H), 5.65 (s, 2H), 4.41-4.03 (m, 3H), 3.18 (s, 3H), 2.59-2.51 (m, 3H), 2.48-2.40 (m, 2H), 2.35-2.22 (m, 1H), 1.86-1.57 (m, 4H); LCMS R_(T)=4.55 min; m/z=420.2 (M+H)⁺.

Example 136

Step 1: 1-benzyl-N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (75 mg, 0.35 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (136 mg, 0.35 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (41 mg, 0.17 mmol) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording 1-benzyl-N-(1-methyl-2-oxo-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-3-yl)-1,2,4-triazole-3-carboxamide (40 mg, 54% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.38 (d, J=7.7 Hz, 1H), 7.46-7.24 (m, 5H), 5.48 (s, 2H), 4.37-4.06 (m, 3H), 3.19 (s, 3H), 2.66-2.52 (m, 3H), 2.48-2.39 (m, 2H), 2.32-2.17 (m, 1H), 1.87-1.59 (m, 4H); LCMS R_(T)=4.35 min; m/z=420.2 (M+H)⁺.

Example 137 Method X3

Step 1: (5S)—N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a solution of (S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (61 mg, 0.26 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (136 mg, 0.35 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min. 3-Amino-1-methyl-4,5,8,9,10,11-hexahydro-3H-[1,3]diazepino[1,2-b]indazol-2-one (41 mg, 0.17 mmol) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording (5S)—N-(1-methyl-2-oxo-2,3,4,5,8,9,10,11-octahydro-1H-[1,3]diazepino[1,2-b]indazol-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (28.3 mg, 34% yield): ¹H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 4.37-4.03 (m, 3H), 3.19 (s, 3H), 3.06-2.95 (m, 1H), 2.84-2.74 (m, 1H), 2.72-2.52 (m, 5H), 2.50-2.40 (m, 3H), 2.28-2.16 (m, 1H), 2.14-2.08 (m, 1H), 1.88-1.55 (m, 5H); LCMS R_(T)=4.84 min; m/z=451.2 (M+H)⁺.

Example 138 Method X4

Step 1: 5-ethoxy-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

To a solution of 5-ethoxy-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (40 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (76 mg, 0.19 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min. (3S)-3-Amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (25 mg, 0.13 mmol) was added. The reaction was stirred at 25° C. for 18 h. The reaction mixture was purified by RP-HPLC affording 5-ethoxy-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide (11.5 mg, 23% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 13.90 (bs, 1H), 9.15 (d, J=7.1 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 7.54-7.46 (m, 1H), 7.40-7.23 (m, 3H), 6.92 (d, J=9.1 Hz, 1H), 5.10-4.95 (m, 1H), 4.72-4.57 (m, 3H), 4.31 (dd, J=11.3, 9.8 Hz, 1H), 3.37 (s, 3H), 1.44 (t, J=7.0 Hz, 3H); LCMS R_(T)=4.80 min; m/z=382.1 (M+H)⁺.

Example 139 Method X5

5-isopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

Step 1: 5-isopropenyl-1H-pyrazolo[4,3-b]pyridine

Bis(tricyclohexylphosphine)palladium(0) (129 mg, 0.19 mmol), 5-chloro-1H-pyrazolo[4,3-b]pyridine (301 mg, 1.9 mmol) and isopropenylboronic acid pinacol ester (471 mg, 2.66 mmol) were mixed in acetonitrile (6.0 mL) and sodium carbonate (2 mol/L) in water (2.9 mL, 5.7 mmol), and the reaction was microwaved at 110° C. for 2 h. The crude mixture was diluted with ethyl acetate and citric acid solution (5% in water) to pH 9, and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in dichloromethane) affording 5-isopropenyl-1H-pyrazolo[4,3-b]pyridine (274 mg, 58% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.27 (s, 1H), 7.96 (dd, J=8.9, 1.0 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 5.91-5.83 (m, 1H), 5.38 (d, J=1.5 Hz, 1H), 2.22 (dd, J=1.5, 0.8 Hz, 3H);

LCMS R_(T)=1.44 min; m/z=160 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 2: 5-isopropyl-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-isopropenyl-1H-pyrazolo[4,3-b]pyridine (201 mg, 0.82 mmol) in ethyl acetate (4.0 mL) and methanol (1.0 mL) was added palladium on activated carbon (10% wt) (86 mg), and the reaction was stirred with H2 balloon at 65° C. for 4 h. The crude mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layers were combined and concentrated to dryness in vacuo, and the crude residue (244 mg) was used without further purification: ¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.18 (s, 1H), 7.91 (dd, J=8.7, 1.1 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 3.15 (hept, J=6.9 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H); LCMS R_(T)=1.18 min; m/z=162 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 3: 3-iodo-5-isopropyl-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-isopropyl-1H-pyrazolo[4,3-b]pyridine (219 mg, 0.96 mmol) in N,N-dimethylformamide (4.85 mL) was added potassium hydroxide (162 mg, 2.9 mmol), followed by iodine (441 mg, 1.74 mmol), and the reaction was stirred at 50° C. for 1 h, and then at 25° C. for 1 h. The crude mixture was diluted with ethyl acetate and washed by sodium sulfite solution till color of organic layer did not change. The aqueous layers were combined and extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in heptane) affording 3-iodo-5-isopropyl-1H-pyrazolo[4,3-b]pyridine (192 mg, 69% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 3.18 (hept, J=6.9 Hz, 1H), 1.29 (d, J=6.9 Hz, 6H); LCMS R_(T)=1.22 min; m/z=288 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 4: methyl 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylate

3-Iodo-5-isopropyl-1H-pyrazolo[4,3-b]pyridine (110 mg, 0.38 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (44 mg, 0.076 mmol) and palladium(II) acetate (8.6 mg, 0.038 mmol) were mixed in triethylamine (0.80 mL, 5.75 mmol), methanol (1.6 mL) and N,N-dimethylformamide (1.2 mL), and the yellow solution was stirred under atmosphere of carbon monoxide at room temperature for 10 min and then at 60° C. for 2 days. The crude mixture was to dryness in vacuo and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in dichloromethane) affording methyl 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylate (96 mg, 114% yield) as off-white powder: ¹H NMR (400 MHz, DMSO-d6) δ 13.95 (bs, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 3.20 (hept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H);

LCMS R_(T)=1.13 min; m/z=220 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 5: 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid

To a solution of methyl 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylate (83 mg, 0.38 mmol) in tetrahydrofuran (2.0 mL), water (1.0 mL) and methanol (1.0 mL) was added sodium hydroxide (150 mg, 3.8 mmol), and the reaction was stirred at 40° C. for 4 h. Hydrochloric acid solution (1.0 M) was added and the final pH was 3. The solution was concentrated to dryness in vacuo, and the crude residue was used without further purification: LCMS R_(T)=1.37 min; m/z=206 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 6: 5-isopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

To a solution of 5-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (40 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (91 mg, 0.23412 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min. (3S)-3-Amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (25 mg, 0.13 mmol) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording 5-isopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4, 3-b]pyridine-3-carboxamide (43.2 mg, 87% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 13.88 (bs, 1H), 9.65 (d, J=7.2 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.55-7.48 (m, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.38-7.26 (m, 3H), 5.04 (dt, J=11.3, 7.3 Hz, 1H), 4.66 (dd, J=9.8, 7.4 Hz, 1H), 4.32 (dd, J=11.3, 9.8 Hz, 1H), 3.37 (s, 3H), 3.30-3.24 (m, 1H), 1.41 (d, J=6.8 Hz, 6H); LCMS R_(T)=4.92 min; m/z=380.2 (M+H)⁺.

Example 140 Method X6

1-benzyl-N-(1-methyl-9,9-dioxido-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-amine

To a solution of 4-cyano-3-tetrahydrothiophenone (1.01 g, 7.78 mmol) in toluene (11.5 mL) was added hydrazine (0.33 mL, 9.7 mmol), and the reaction was stirred at 90° C. for 10 h. The reaction mixture was concentrated to dryness in vacuo and the residue was used without further purification: LCMS R_(T)=1.29 min; m/z=170 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 2: N-(4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)formamide

4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-amine (442 mg, 2.98 mmol) and formic acid (1.3 mL) were mixed together, and the reaction was stirred at 110° C. for 3 h. The crude reaction mixture was diluted with ethyl acetate (300 mL) and water (30 mL), and sodium hydroxide solution (aq, 50% w/w) was added dropwise at 0° C. to change the pH of aqueous layer to 7. The two layers were separated. The aqueous layer was extracted by ethyl acetate (50 mL×2). The organic layers were combined, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue (2.68 g yellow solid) was used without further purification: LCMS R_(T)=1.39 min; m/z=170 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 3: N-methyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine

To a solution of N-(4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)formamide (2.68 g, 15.8 mmol) in tetrahydrofuran (201 mL) was added lithium aluminum hydride (2 mol/L) in tetrahydrofuran (23.8 mL, 47.5 mmol) at 0° C., and the reaction was stirred at 25° C. for 2.5 h, resulting in a brown solution. Sodium sulfate decahydrate was added, and the mixture was stirred for 18 h. The mixture was filtered through celite, and ethyl acetate was used to rinse the celite solid. The combined liquid was concentrated to dryness in vacuo, and the crude residue (3.43 g) was used without further purification: LCMS R_(T)=1.58 min; m/z=156 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 4: 4-chloro-N-[1-(4-chlorobutanoyl)-4,6-dihydrothieno[3,4-c]pyrazol-3-yl]-N-methyl-butan amide

To a solution of N-methyl-4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-amine (3.43 g, 22.1 mmol) and N,N-dimethylpyridin-4-amine (270 mg, 2.21 mmol) in dichloromethane (88 mL) and N,N-diisopropylethylamine (7.71 mL, 44.2 mmol) was added 4-chlorobutyryl chloride (4.47 mL, 39.8 mmol) at 0° C., and the reaction was stirred at 0° C. for 30 min then at 25° C. for 2 h. The reaction solution was diluted with ethyl acetate (350 mL), and washed by water (final pH˜7). The organic layer was dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in heptane) affording 4-chloro-N-[1-(4-chlorobutanoyl)-4,6-dihydrothieno[3,4-c]pyrazol-3-yl]-N-methyl-butanamide (3.785 g, 47% yield) as yellow oil: LCMS R_(T)=3.46 min; m/z=364 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 5: 4-chloro-N-(4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)-N-methyl-butanamide

To a solution of 4-chloro-N-[1-(4-chlorobutanoyl)-4,6-dihydrothieno[3,4-c]pyrazol-3-yl]-N-methyl-butanamide (3.78 g, 10.4 mmol) in ethanol (16 mL) was added sodium hydroxide (1 mol/L) in water (10 mL, 10 mmol), and the reaction was stirred at 0° C. for 15 min. The crude mixture was diluted with ethyl acetate and water, and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude material (3.40 g white solid) was used without further purification: LCMS R_(T)=1.87 min; m/z=260 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 6: 1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 4-chloro-N-(4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)-N-methyl-butanamide (2.70 g, 10.4 mmol) in N,N-dimethylformamide (47 mL) was added cesium carbonate (4.41 g, 13.5 mmol), and the reaction was stirred at 60° C. for 1.5 h. The crude mixture was diluted with ethyl acetate and citric acid to pH 8, and the two layers were separated. The aqueous layer was extracted by ethyl acetate twice. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) affording 1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (1.91 g, 62% yield) as slightly yellow oil, which crystallized upon scratch or addition of crystal seed: ¹H NMR (400 MHz, DMSO-d6) δ 4.14 (t, J=6.7 Hz, 2H), 3.88 (s, 4H), 3.12 (s, 3H), 2.33-2.15 (m, 4H); ¹H NMR (400 MHz, Chloroform-d) δ 4.21 (t, J=6.8 Hz, 2H), 4.03-3.95 (m, 2H), 3.89-3.82 (m, 2H), 3.23 (s, 3H), 2.50-2.30 (m, 4H); LCMS R_(T)=1.66 min; m/z=224 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 7: 3-iodo-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (1001 mg, 3.3621 mmol, 75% wt purity) in dichloromethane (28 mL) was added N,N,N′,N′-tetramethylethylenediamine (4.05 mL, 27 mmol) at −20° C. (acetone-dry-ice bath), followed by iodotrimethylsilane (3.84 mL, 27 mmol), and the reaction was stirred in acetone-dry-ice bath (−20˜−15° C.) for 3 h. Iodine (3.41 g, 13.5 mmol) was added, and the reaction was stirred in acetone-dry-ice bath (at −15˜−10° C.) for 2 h. The crude mixture was diluted with ethyl acetate and sodium thiosulfate solution (10% aq., 10 mL), and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in heptane) affording 3-iodo-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (0.80 g, 68% yield) as off-white solid: ¹H NMR (400 MHz, Chloroform-d) δ 4.65 (dd, J=8.5, 7.6 Hz, 1H), 4.19 (ddd, J=8.3, 5.9, 1.5 Hz, 2H), 4.03-3.95 (m, 2H), 3.93-3.85 (m, 2H), 3.29 (s, 3H), 3.05-2.89 (m, 1H), 2.85-2.71 (m, 1H); LCMS R_(T)=1.97 min; m/z=350 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 8: 3-azido-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 3-iodo-1-methyl-1,4, 5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (310 mg, 0.89 mmol) in N,N-dimethylformamide (3.50 mL) was added sodium azide (89 mg, 1.33 mmol), and the reaction was stirred at 25° C. for 2 h. The reaction mixture was concentrated to dryness in vacuo and was diluted with ethyl acetate and water (pH-8). The two layers were separated. The aqueous layer was extracted by ethyl acetate twice. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude material (436 mg) was used without further purification: LCMS R_(T)=1.07 min; m/z=265 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 9: 3-azido-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one 9,9-dioxide

To a solution of 3-azido-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′: 3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (355 mg, 1.34 mmol) in acetic acid (0.081 mL, 1.41 mmol) and dichloromethane (11 mL) was added 3-chloroperoxybenzoic acid (722 mg, 3.22 mmol) at 0° C., and the reaction was stirred at 0° C. for 1 h. Second portion of 3-chloroperoxybenzoic acid (96 mg, 0.43 mmol) was added, and the reaction was stirred at 25° C. for 30 min. The crude mixture was diluted with ethyl acetate. The organic solution was washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate in heptane) affording 3-azido-1-methyl-1,4, 5,10-tetrahydro-8H-thieno[3′,4′: 3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one 9,9-dioxide (360 mg, 90% yield) as white solid: ¹H NMR (400 MHz, Chloroform-d) δ 4.55-4.39 (m, 1H), 4.33-4.16 (m, 5H), 3.91 (dd, J=10.6, 7.9 Hz, 1H), 3.32 (s, 3H), 2.88-2.74 (m, 1H), 2.30 (dddd, J=13.5, 10.7, 6.6, 1.8 Hz, 1H); ¹H NMR (400 MHz, DMSO-d6) δ 4.53 (d, J=14.7 Hz, 1H), 4.48-4.25 (m, 5H), 4.13 (dd, J=11.3, 7.9 Hz, 1H), 3.25 (s, 3H), 2.84-2.64 (m, 1H), 2.17 (dddd, J=13.2, 11.4, 6.1, 1.7 Hz, 1H); LCMS R_(T)=1.52 min; m/z=297 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 10: 3-amino-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one 9,9-dioxide

To a suspension of 3-azido-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one 9,9-dioxide (291 mg, 0.84 mmol) in tetrahydrofuran (6.9 mL) and water (0.93 mL) was added polymer-bound triphenylphosphine (5.1 mmol), and the reaction was stirred at 25° C. for 12 h. The reaction mixture was filtered through celite, and the celite solid was rinsed by a solution of methanol in dichloromethane (10% v/v) twice. The solutions were combined and concentrated to dryness in vacuo, and the crude material (284 mg) was used without further purification: LCMS R_(T)=0.52 min; m/z=271 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins).

Step 11: 1-benzyl-N-(1-methyl-9,9-dioxido-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (68 mg, 0.32 mmol) in N,N-dimethylformamide (1.0 mL) and N,N-diisopropylethylamine (0.055 mL, 0.32 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (123 mg, 0.32 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min, resulting in a yellow solution. 3-Amino-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one 9,9-dioxide (57 mg, 0.21 mmol) was added. The reaction was stirred at 25° C. for 18 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording 1-benzyl-N-(1-methyl-9,9-dioxido-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazol o[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (61 mg, 63% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.49 (d, J=7.7 Hz, 1H), 7.46-7.23 (m, 5H), 5.49 (s, 2H), 4.56-4.33 (m, 6H), 4.34-4.19 (m, 1H), 3.20 (s, 3H), 2.73-2.60 (m, 1H), 2.41-2.28 (m, 1H); LCMS R_(T)=3.47 min; m/z=456.1 (M+H)⁺.

Example 141

5-benzyl-N-(1-methyl-9,9-dioxido-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide Step 1: 5-benzyl-N-(1-methyl-9,9-dioxido-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

To a suspension of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (65 mg, 0.32 mmol) in N,N-dimethylformamide (1.0 mL) and N,N-diisopropylethylamine (0.052 mL, 0.32 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (123 mg, 0.32 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min, resulting in a yellow solution. 3-Amino-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one 9,9-dioxide (57 mg, 0.21 mmol) was added. The reaction was stirred at 25° C. for 18 h. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by RP-HPLC affording 5-benzyl-N-(1-methyl-9,9-dioxido-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazol o[1,5-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (8 mg, 8.3% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 8.47 (bs, 1H), 7.40-7.17 (m, 5H), 4.56-4.33 (m, 6H), 4.33-4.20 (m, 1H), 4.10 (s, 2H), 3.20 (s, 3H), 2.75-2.59 (m, 1H), 2.41-2.29 (m, 1H);

LCMS R_(T)=3.42 min; m/z=456.1 (M+H)⁺.

Example 142 Method X7

1-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 3-amino-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 3-azido-1-methyl-1,4, 5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (235 mg, 0.89 mmol) in tetrahydrofuran (3.0 mL) and water (1.0 mL) was added polymer-bound triphenylphosphine, (5.4 mmol), and the reaction was stirred at 25° C. for 5 h. The reaction mixture was filtered through celite, and the celite solid was rinsed by a solution of methanol in dichloromethane (10% v/v, 3 mL) twice. The organic solutions were combined and concentrated to dryness in vacuo, and the crude material (285 mg) was used without further purification: LCMS R_(T)=1.3 min; m/z=239 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 2: 1-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (71 mg, 0.33 mmol) in N,N-dimethylformamide (1.0 mL) and N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (129 mg, 0.33 mmol) at 0° C., and the reaction was stirred at 0° C. for 20 min, resulting in a yellow solution. 3-Amino-1-methyl-1,4,5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (53 mg, 0.22 mmol) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording 1-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (75 mg, 80% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.45 (d, J=7.7 Hz, 1H, NH), 7.44-7.26 (m, 5H), 5.48 (s, 2H), 4.40 (dt, J=11.4, 7.8 Hz, 1H), 4.31-4.12 (m, 2H), 3.99-3.78 (m, 4H), 3.19 (s, 3H), 2.73-2.56 (m, 1H), 2.37-2.21 (m, 1H); LCMS R_(T)=3.99 min; m/z=424.1 (M+H)⁺.

Example 143 Method X8

5-chloro-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

Step 1: 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (501 mg, 3.16 mmol) in N,N-dimethylformamide (16 mL) was added potassium hydroxide (532 mg, 9.49 mmol), followed by iodine (1.45 g, 5.70 mmol) at 0° C., and the reaction was stirred at 0° C. for 30 min, then at 25° C. for 30 min, and finally at 50° C. for 1 h. The crude mixture was diluted with ethyl acetate and washed by sodium sulfite solution till color of organic layer did not change. The aqueous layers were combined and extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo affording 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (770 mg, 87% yield) used without further purification: ¹H NMR (400 MHz, DMSO-d6) δ 13.89 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H); LCMS R_(T)=1.92 min; m/z=280 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 2: methyl 5-chloro-1H-pyrazolo[4,3-b]pyridine-3-carboxylate

5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (250 mg, 0.85 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (49 mg, 0.085 mmol,) and palladium(II) acetate (9.5 mg, 0.042 mmol) were mixed in triethylamine (2.6 mL), methanol (2.6 mL) and N,N-dimethylformamide (2.5 mL), and the yellow solution was stirred under atmosphere of carbon monoxide at room temperature for 10 min and then at 70° C. for 2 days. The crude mixture was concentrated to dryness in vacuo, and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in dichloromethane) affording methyl 5-chloro-1H-pyrazolo[4,3-b]pyridine-3-carboxylate (0.12 g, 67% yield) as off-white powder: ¹H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 3.92 (s, 3H); LCMS R_(T)=1.48 min; m/z=212 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 3: 5-chloro-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid

To a solution of methyl 5-chloro-1H-pyrazolo[4,3-b]pyridine-3-carboxylate (30.0 mg, 0.142 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.25 mL) was added sodium hydroxide (1 mol/L) in water (0.25 mL), and the reaction was stirred at 25° C. for 8 h. Hydrochloric acid solution (1.0 M, 0.60 mL) was added, resulting in a clear solution with pH ˜6. The solution was concentrated to dryness in vacuo, and the crude material was used without further purification:

LCMS R_(T)=0.91 min; m/z=198 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 4: 5-chloro-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (35 mg, 0.18 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (70 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.042 mL) at 0° C., and the reaction was stirred at 0° C. for 20 min. (3S)-3-Amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mmol) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording 5-chloro-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide (12 mg, 27% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 14.22 (bs, 1H), 8.75 (d, J=7.3 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.52 (dd, J=6.9, 2.5 Hz, 1H), 7.39-7.24 (m, 3H), 4.97 (dt, J=11.4, 7.4 Hz, 1H), 4.59 (dd, J=9.9, 7.5 Hz, 1H), 4.44 (dd, J=11.4, 9.9 Hz, 1H), 3.36 (s, 3H); LCMS R_(T)=4.37 min; m/z=372.1 (M+H)⁺.

Example 144 Method X9

5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

Step 1: 5-bromo-1H-pyrazolo[4,3-b]pyridine

To a suspension of 5-chloro-1H-pyrazolo[4,3-b]pyridine (81 mg, 0.51 mmol) in propionitrile (0.51 mL) was added bromotrimethylsilane (0.135 mL, 1.0 mmol), and the reaction was stirred at 100° C. for 16 h. Second portion of bromotrimethylsilane (0.14 mL, 1.0 mmol) was added, and the suspension was stirred at 110° C. for 6 h. The crude mixture was quenched with ice-water. Sodium carbonate was added to change the pH to 9. The aqueous layer was extracted by a solution of methanol in ethyl acetate (10% v/v) twice. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude material (189 mg beige solid) was used without further purification: ¹H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.29 (d, J=1.0 Hz, 1H), 8.02 (dd, J=8.7, 1.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H); LCMS R_(T)=1.63 min; m/z=198 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 2: 5-cyclopropyl-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-bromo-1H-pyrazolo[4,3-b]pyridine (77 mg, 0.37 mmol), palladium(II) acetate (8.3 mg, 0.037 mmol) and S-Phos (31 mg, 0.074 mmol) in tetrahydrofuran (1.5 mL) was added cyclopropylzinc bromide (0.5 mol/L) in tetrahydrofuran (4 mL, 2.2 mmol), and the reaction was stirred at 110° C. for 18 h. The crude mixture was diluted with ethyl acetate and citric acid solution (10% aq.) to pH 9, and the two layers were separated. The aqueous layer was extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in dichloromethane) to afford 5-cyclopropyl-1H-pyrazolo[4,3-b]pyridine (33 mg, 56% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 13.12 (bs, 1H), 8.10 (s, 1H), 7.93-7.82 (m, 1H), 7.28 (d, J=8.7 Hz, 1H), 2.27-2.16 (m, 1H), 0.99-0.92 (m, 4H); LCMS R_(T)=1.06 min; m/z=160 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 3: 5-cyclopropyl-3-iodo-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-cyclopropyl-1H-pyrazolo[4,3-b]pyridine (290 mg, 1.82 mmol) in N,N-dimethylformamide (9.26 mL) was added potassium hydroxide (307 mg, 5.52 mmol), followed by iodine (832 mg, 3.3 mmol) at 25° C., and the reaction was stirred at 50° C. for 1 h. The crude mixture was diluted with ethyl acetate and washed by sodium sulfide solution till color of organic layer did not change. The aqueous layers were combined and extracted by ethyl acetate. The organic layers were combined, washed by water and brine, dried over magnesium sulfate, filtered through celite, and concentrated to dryness in vacuo. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in dichloromethane) affording 5-cyclopropyl-3-iodo-1H-pyrazolo[4,3-b]pyridine (122 mg, 23% yield) as white solid: ¹H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 2.30-2.20 (m, 1H), 1.05-0.93 (m, 4H); R_(T)=1.22 min; m/z=286 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 4: 5-cyclopropyl-3-iodo-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine and 5-cyclopropyl-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

To a suspension of 5-cyclopropyl-3-iodo-1H-pyrazolo[4,3-b]pyridine (67 mg, 0.23 mmol) in dichloromethane (2.0 mL) was added 4-methylbenzenesulfonamide hydrate (4.45 mg, 0.023 mmol), followed by 3,4-dihydro-2H-pyran (59 mg, 0.70 mmol), and the reaction was stirred at 25° C. for 18 h, resulting in a colorless solution. More 3,4-dihydro-2H-pyran (59 mg, 0.705 mmol) was added, and the reaction solution was kept at 40° C. for 3.5 h. The solution was concentrated to dryness in vacuo, and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% dichloromethane in heptane) affording 5-cyclopropyl-3-iodo-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (31 mg, 36% yield) and 5-cyclopropyl-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (15 mg, 18% yield):

Analytical data for one isomer: ¹H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=9.0 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 5.88-5.78 (m, 1H), 4.02-3.90 (m, 1H), 3.78-3.65 (m, 1H), 2.49-2.38 (m, 1H), 2.30-2.16 (m, 1H), 2.13-1.91 (m, 1H), 1.83-1.39 (m, 3H), 1.06-0.93 (m, 4H); LCMS R_(T)=1.47 min; m/z=370 (M+H)⁺.

Analytical data for the other isomer: ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 5.83 (dd, J=9.7, 2.4 Hz, 1H), 3.91-3.83 (m, 1H), 3.78-3.65 (m, 1H), 2.38-2.21 (m, 2H), 2.07-1.91 (m, 2H), 1.79-1.40 (m, 3H), 1.07-0.91 (m, 4H); LCMS R_(T)=1.62 min; m/z=370 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Note: following Step 5 and 6 below, both isomers afforded 5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide (i.e., final product).

Step 5: 5-cyclopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

5-cyclopropyl-3-iodo-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (31 mg, 0.084 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one hydrochloride (29 mg, 0.13 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.3 mg, 0.013 mmol) and palladium(II) acetate (1.9 mg, 0.0084 mmol) were mixed in triethylamine (0.076 mL), N,N-dimethylformamide (0.10 mL) and toluene (5 mL), and the yellow solution was stirred under atmosphere of carbon monoxide at room temperature for 10 min and then at 80° C. for 18 h. The crude mixture was concentrated to dryness in vacuo, and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% ethyl acetate in dichloromethane) affording 5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine-3-carboxamide (20 mg, 52% yield) as light brown solid:

LCMS R_(T)=3.30 min; m/z=462 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.05% formic acid over 5 mins)

Step 6: 5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

To a solution of 5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine-3-carboxamide (20 mg, 0.043 mmol) in methanol (0.26 mL) and dichloromethane (0.50 mL) was added hydrochloride (4 mol/L) in 1,4-dioxane (0.12 mL, 0.48 mmol), and the reaction was stirred at 25° C. for 1 h. N,N-diisopropylethylamine (0.11 mL) was added. The crude mixture was concentrated to dryness in vacuo. The crude material was purified by RP-HPLC affording 5-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-pyrazolo[4,3-b]pyridine-3-carboxamide (13.2 mg, 81% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 9.50 (d, J=7.2 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.55-7.48 (m, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.38-7.27 (m, 3H), 5.01 (dt, J=11.3, 7.3 Hz, 1H, CHN), 4.64 (dd, J=9.8, 7.4 Hz, 1H), 4.29 (dd, J=11.3, 9.9 Hz, 1H), 3.38 (s, 3H), 2.41-2.28 (m, 1H, Ar—CH), 1.43-1.33 (m, 1H), 1.27-1.17 (m, 1H), 1.15-1.05 (m, 2H); LCMS R_(T) '² 4.73 min; m/z=378.2 (M+H)⁺.

Example 145

5-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide Step 1: 5-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

To a solution of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (113 mg, 0.556 mmol) in N,N-dimethylformamide (1.5 mL) and N,N-diisopropylethylamine (0.0776 mL, 0.44 mmol) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (216 mg, 0.56 mmol,) at 0° C., and the reaction was stirred at 0° C. for 20 min, resulting in a brown solution. 3-Amino-1-methyl-1,4, 5,10-tetrahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-2(3H)-one (53 mg, 0.22 mmol) was added. The reaction was stirred at 25° C. for 18 h. The crude material was purified by RP-HPLC affording 5-benzyl-N-(1-methyl-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (54 mg, 57% yield) as white powder: ¹H NMR (400 MHz, DMSO-d6) δ 14.40 (bs, 1H), 8.48 (bs, 1H), 7.42-7.16 (m, 5H), 4.40 (dt, J=11.4, 7.8 Hz, 1H), 4.32-4.15 (m, 2H), 4.11 (s, 2H), 4.02-3.78 (m, 4H), 3.19 (s, 3H), 2.69-2.56 (m, 1H), 2.40-2.25 (m, 1H); LCMS R_(T)=3.87 min; m/z=424.1 (M+H)⁺.

Examples 146-170 were prepared according to the Methods above and were purified according the Chiral Methods section below. Table 2 provides data for these compounds.

Chiral Methods

Example # SFC analytical method SFC prep method 149 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD 150 × 21.2 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min Isocratic: 25% B in 6 min Flow rate: Column temperature: 40 oC, 70 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar 147 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD150 × 21.2 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min Isocratic: 25% B in 6 min Flow rate: Column temperature: 40 oC, 70 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar 148 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD150 × 21.2 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min Isocratic: 25% B in 6 min Flow rate: Column temperature: 40 oC, 70 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar 150 SFC condition: Column: Chiralcel OX SFC condition: Column: Chiralcel 50 × 4.6 mm I.D., 3 μm Mobile phase: OJ 250 × 21.1 mm I.D., 5 μm Mobile A: CO2 B: Methanol (0.1% NH4OH) phase: A: CO2 B: Methanol (0.1% Gradient: 5-60% B in 2.5 min Flow rate: NH4OH) Isocratic: 20% in 10 min 4 mL/min Column temperature: 40 oC, B Flow rate: 70 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 149 SFC condition: Column: Chiralcel OX SFC condition: Column: Chiralcel 50 × 4.6 mm I.D., 3 μm Mobile phase: OJ 250 × 21.1 mm I.D., 5 μm Mobile A: CO2 B: Methanol (0.1% NH4OH) phase: A: CO2 B: Methanol (0.1% Gradient: 5-60% B in 2.5 min Flow rate: NH4OH) Isocratic: 20% B in 10 4 mL/min Column temperature: 40 oC, min Flow rate: 70 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 153 SFC condition: Column: Chiralcel OX SFC condition: Column: Chiralcel 50 × 4.6 mm I.D., 3 μm Mobile phase: OJ 250 × 21.1 mm I.D., 5 μm Mobile A: CO2 B: Methanol (0.1% NH4OH) phase: A: CO2 B: Methanol (0.1% Gradient: 5-60% B in 2.5 min Flow rate: NH4OH) Isocratic: 15% B in 10 4 mL/min Column temperature: 40 oC, min Flow rate: 70 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 152 SFC condition: Column: Chiralcel OX SFC condition: Column: Chiralcel 50 × 4.6 mm I.D., 3 μm Mobile phase: OJ 250 × 21.1 mm I.D., 5 μm Mobile A: CO2 B: Methanol (0.1% NH4OH) phase: A: CO2 B: Methanol (0.1% Gradient: 5-60% B in 2.5 min Flow rate: NH4OH) Isocratic: 15% B in 10 4 mL/min Column temperature: 40 oC, min Flow rate: 70 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 154 SFC condition: Column: Chiralcel OX SFC condition: Column: Chiralcel 50 × 4.6 mm I.D., 3 μm Mobile phase: OX 250 × 21.2 mm I.D., 5 μm A: CO2 B: Methanol (0.1% NH4OH) Mobile phase: A: CO2 B: Methanol Gradient: 5-60% B in 2.5 min (0.1% NH4OH) Isocratic: 40% B Flow rate: 4 mL/min in 6 min Flow rate: 70 mL/min Column temperature: 40 oC, Column temperature: 40 oC, BPR: 120 bar BPR: 100 bar 156 SFC condition: Column: Chiralcel OX SFC condition: Column: Chiralcel 50 × 4.6 mm I.D., 3 μm Mobile phase: OX 250 × 21.2 mm I.D., 5 μm A: CO2 B: Methanol (0.1% NH4OH) Mobile phase: A: CO2 B: Methanol Gradient: 5-60% B in 2.5 min (0.1% NH4OH) Isocratic: 40% B Flow rate: 4 mL/min in 6 min Flow rate: 70 mL/min Column temperature: 40 oC, Column temperature: 40 oC, BPR: 120 bar BPR: 100 bar 155 SFC condition: Column: Chiralpak AD SFC condition: Column: Chiralpak 50 × 4.6 mm I.D., 3 μm Mobile phase: AD 150 × 21.2 mm I.D., 5 μm A: CO2 B: Methanol (0.1% NH4OH) Mobile phase: A: CO2 B: Methanol Gradient: 5-60% B in 2.5 min (0.1% NH4OH) Isocratic: 30% B Flow rate: 4 mL/min in 6 min Flow rate: 70 mL/min Column temperature: 40 oC, Column temperature: 40 oC, BPR: 120 bar BPR: 100 bar 161 SFC condition: Column: Phenomenex SFC condition: Column: Lux Cellulose-3 50 × 4.6 mm I.D., Phenomenex Lux Cellulose-3 3 μm Mobile phase: A: CO2 B: 150 × 21.2 mm I.D., 5 μm Methanol (0.1% NH4OH) Gradient: Mobile phase: A: CO2 B: Methanol 5-60% B in 2.5 min Flow rate: (0.1% NH4OH) Isocratic: 15% B in 4 mL/min Column temperature: 40 oC, 6 min Flow rate: 70 mL/min BPR: 120 bar Column temperature: 40 oC, BPR: 100 bar 168 SFC condition: Column: Phenomenex SFC condition: Column: Lux Cellulose-3 50 × 4.6 mm I.D., Phenomenex Lux Cellulose-3 3 μm Mobile phase: A: CO2 B: 150 × 21.2 mm I.D., 5 μm Methanol (0.1% NH4OH) Mobile phase: A: CO2 B: Methanol Gradient: 5-60% B in 2.5 min (0.1% NH4OH) Isocratic: 15% B in Flow rate: 4 mL/min 6 min Flow rate: 70 mL/min Column temperature: 40 oC, Column temperature: 40 oC, BPR: 120 bar BPR: 100 bar 159 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD 150 × 30 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min Gradient: 5-60% B in 6 min Flow Column temperature: 40 oC, rate: 100 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 169 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AS 150 × 30 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min Gradient: 5-60% B in 6 min Flow Column temperature: 40 oC, rate: 100 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 170 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD 150 × 30 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min 5-60% B in 10 min Flow rate: Column temperature: 40 oC, 100 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar 162 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD 150 × 30 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min 5-60% B in 10 min Flow rate: Column temperature: 40 oC, 100 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar 157 SFC condition: Column: Chiralpak AD SFC condition: Column: Chiralpak 50 × 4.6 mm I.D., 3 μm Mobile phase: AD 150 × 30.0 mm I.D., 5 μm A: CO2 B: Methanol (0.1% NH4OH) Mobile phase: A: CO2 B: Methanol Gradient: 5-60% B in 2.5 min (0.1% NH4OH) Isocratic: 35% B Flow rate: 4 mL/min in 6 min Flow rate: 150 mL/min Column temperature: 40 oC, Column temperature: 25 oC, BPR: 120 bar BPR: 100 bar 167 SFC condition: Column: Chiralpak AD SFC condition: Column: Chiralpak 50 × 4.6 mm I.D., 3 μm Mobile phase: AD 150 × 30.0 mm I.D., 5 μm A: CO2 B: Methanol (0.1% NH4OH) Mobile phase: A: CO2 B: Methanol Gradient: 5-60% B in 2.5 min (0.1% NH4OH) Isocratic: 35% B Flow rate: 4 mL/min in 6 min Flow rate: 150 mL/min Column temperature: 40 oC, Column temperature: 25 oC, BPR: 120 bar BPR: 100 bar 163 SFC condition: Column: Chiralcel OX SFC condition: Column: 50 × 4.6 mm I.D., 3 μm Mobile phase: Cellulose-1 150 × 21.1 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min Isocratic: 25% B in 10 min Flow Column temperature: 40 oC, rate: 70 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 160 SFC condition: Column: Chiralcel OX SFC condition: Column: 50 × 4.6 mm I.D., 3 μm Mobile phase: Cellulose-1 150 × 21.1 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min Isocratic: 30% B in 10 min Flow Column temperature: 40 oC, rate: 70 mL/min Column BPR: 120 bar temperature: 40 oC, BPR: 100 bar 166 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD 150 × 30 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min 5-60% B in 10 min Flow rate: Column temperature: 40 oC, 100 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar 158 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD 150 × 30 mm ID., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min 5-60% B in 10 min Flow rate: Column temperature: 40 oC, 100 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar 165 SFC condition: Column: Chiralcel OX SFC condition: Column: ES 50 × 4.6 mm I.D., 3 μm Mobile phase: Industries AD 150 × 30 mm I.D., A: CO2 B: Methanol (0.1% NH4OH) 5 μm Mobile phase: A: CO2 B: Gradient: 5-60% B in 2.5 min Methanol (0.1% NH4OH) Flow rate: 4 mL/min 5-60% B in 10 min Flow rate: Column temperature: 40 oC, 100 mL/min Column temperature: BPR: 120 bar 40 oC, BPR: 100 bar

Example 171 WX Method ZZZ

(S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: (S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one and (R)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one was underwent SFC separation to get peak 1 as (S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5 (6H)-one and peak 2 as (R)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one.

SFC condition: Column: Chiralpak OD 250×30 mm I.D., 5 μm Mobile phase: A: CO₂ B: Ethanol (0.05% NH₄OH) Isocratic: 20% B in 6 min Flow rate: 50 mL/min Column temperature: 40° C., BPR: 100 bar (Peak 1: 3.11 min) (Peak 2: 3.53 min).

Step 2: (S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (200 mg, 0.91 mmol), 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (0.19 g, 0.91 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (180 mg, 1.36 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (260 mg, 1.36 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.1% HCl in water) to afford (S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (120 mg, 32%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 7.41-7.28 (m, 5H), 6.06 (s, 1H), 5.48 (s, 2H), 4.34-4.22 (m, 2H), 4.12-4.04 (m, 1H), 3.19 (s, 3H), 2.61-2.54 (m, 1H), 2.37-2.29 (m, 1H), 1.88-1.81 (m, 1H), 0.89-0.81 (m, 2H), 0.70-0.61 (m, 2H). LCMS R_(T)=0.98 min; m/z=406.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.98 min, ESI+ found [M+H]=406.2.

WX Method B

7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide)

Step 1: methyl 2-(4-bromopyridin-2-yl) acetate

A mixture of 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (2.2 g, 11.5 mmol), 4-bromopyridinen-oxide (1.0 g, 5.7 mmol), N,N-diisopropylethylamine (2.2 g, 17.2 mmol) and bromo[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate (3.0 g, 6.3 mmol) in tetrahydrofuran (20 mL) was stirred at 25° C. for 1 h and then diluted with ethyl acetate (30 mL). The resulting mixture was washed with water (3×30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford methyl 2-(4-bromopyridin-2-yl) acetate (1.0 g, 75%): LCMS R_(T)=0.52 min; m/z=232.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.520 min, ESI+ found [M+H]=232.0

Step 2: (E)-methyl 2-(4-bromopyridin-2-yl)-2-(hydroxyimino) acetate

To a solution of methyl 2-(4-bromopyridin-2-yl) acetate (4.0 g, 17.4 mmol) in acetic acid (60 mL) was added sodium nitrite (1.2 g, 17.4 mmol) in water (30 mL) at 0° C. After addition, the mixture was stirred at 25° C. for 40 min. Water (30 mL) was added and the mixture was stirred for an additional 1 h. The reaction was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate (100 mL), washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to afford (E)-methyl 2-(4-bromopyridin-2-yl)-2-(hydroxyimino) acetate (3.6 g, 80%) as yellow oil: LCMS R_(T)=0.65 min; m/z=261.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.651 min, ESI+ found [M+H]=261.0

Step 3: methyl 2-amino-2-(4-bromopyridin-2-yl) acetate

A mixture of zinc (1.8 g, 27.8 mmol) and (E)-methyl 2-(4-bromopyridin-2-yl)-2-(hydroxyimino) acetate (3.6 g, 13.9 mmol) in methanol (56 mL) and water (36 mL) was slowly added formic acid (36 mL, 961.9 mmol) over 30 min at 0° C. After addition, the mixture was stirred at 25° C. for 5 h and then diluted with ethyl acetate (50 mL). The organic layer was washed with water (3×30 mL). The combined aqueous layers were concentrated under reduced pressure to afford crude methyl 2-amino-2-(4-bromopyridin-2-yl) acetate (3.0 g, 88%) as yellow oil, used as is in the next step without further purification.

Step 4: methyl 7-bromoimidazo[1,5-a]pyridine-1-carboxylate

A mixture of methyl 2-amino-2-(4-bromo-2-pyridyl) acetate (500 mg, 2.0 mmol) and triethyl orthoformate (2 mL, 2.0 mmol) was heated at 150° C. under microwave conditions for 10 min. The mixture was concentrated under reduced pressure and purified by preparative TLC (50% ethyl acetate in petroleum ether) to afford methyl 7-bromoimidazo[1,5-a]pyridine-1-carboxylate (210 mg, 40%) as brown oil: LCMS R_(T)=0.65 min; m/z=257.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.654 min, ESI+ found [M+H]=257.0

Step 5: methyl 7-methylimidazo[1,5-a]pyridine-1-carboxylate

A mixture of methyl 7-bromoimidazo[1,5-a]pyridine-1-carboxylate (210 mg, 0.8 mmol), potassiumcarbonate (227 mg, 1.7 mmol) and trimethylboroxine (310 mg, 2.5 mmol) in 1,4-dioxane (5 mL) was treated with tetrakis(triphenylphosphine) palladium(0) (47 mg, 0.04 mmol). The resulting mixture was heated to 120° C. for 4 h under nitrogen. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) to afford methyl 7-methylimidazo[1,5-a]pyridine-1-carboxylate (110 mg, 70%) as a yellow solid, used in the next step without further purification.

Step 6: methyl 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate

A mixture of methyl 7-methylimidazo[1,5-a]pyridine-1-carboxylate (90 mg, 0.47 mmol) and 10% palladium on carbon (50 mg, 0.05 mmol) in methanol (10 mL) was hydrogenated (50 psi) at 25° C. for 18 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (7% methanol in dichloromethane) affording methyl 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate (50 mg, 54%) as yellow oil: LCMS R_(T)=1.24 min; m/z=195.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.239 min, ESI+ found [M+H]=195.1

Step 7: 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid

To a solution of methyl 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate (18 mg, 0.09 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added lithium hydroxide (11 mg, 0.46 mmol). The resulting mixture was stirred at 25° C. for 12 h, adjusted to pH=4 by addition of hydrochloric acid (1.0 M) and concentrated under reduced pressure. The residue was extracted with dichloromethane (30 mL) and ethyl acetate (1×30 mL). The combined organic layers were concentrated under reduced pressure to afford 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid (15 mg, 90%) as white solids, used in the next step without further purification.

Step 8: 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide

To a solution of 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid (22 mg, 0.12 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (76 mg, 0.15 mmol). The resulting mixture was stirred for 12 h at 25° C. and then concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (27-57% methanol in water and 0.05% ammonia hydroxide) to afford 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide (6.6 mg, 15%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.55-7.53 (m, 1H), 7.43-7.41 (m, 1H), 7.32-7.29 (m, 2H), 7.11-6.92 (m, 1H), 4.97-4.96 (m, 1H), 4.59-4.55 (m, 1H), 4.35-4.21 (m, 2H), 3.94-3.93 (m, 1H), 3.42-3.41 (m, 3H), 3.31-3.24 (m, 1H), 2.41-2.34 (m, 1H), 2.01-1.98 (m, 2H), 1.63-1.59 (m, 1H), 1.12-1.09 (m, 3H). LCMS R_(T)=0.74 min; m/z=355.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.740 min, ESI+ found [M+H]=355.0.

Example 172 WX Method PP

(S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyltriazole-4-carboxylic acid (20 mg, 0.10 mmol), (S)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (15 mg, 0.08 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (22 mg, 0.11 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (19 mg, 0.11 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium bicarbonate in water) to afford (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (12.1 mg, 39%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 7.39-7.29 (m, 5H), 6.13 (s, 1H), 5.49 (s, 2H), 4.15-4.10 (m, 2H), 4.08-4.06 (m, 1H), 3.21 (s, 3H), 2.59-2.54 (m, 1H), 2.35-2.29 (m, 1H), 2.16 (s, 3H). LCMS R_(T)=0.909 min; m/z=380.4 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.909 min, ESI+ found [M+H]=380.4.

Example 173 WX Method D

6-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide

Step 1: 6-(prop-1-en-2-yl)imidazo[1,5-a]pyridine

A mixture of 6-bromoimidazo[1,5-a]pyridine (500 mg, 2.5 mmol), potassium isopropyl trifluoroborate (750 mg, 5.0 mmol), cesium carbonate (1.654 g, 5.0 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (185 mg, 0.1 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was heated at 80° C. for 3 h under nitrogen. After cooled, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with preparative TLC (10% methanol in dichloromethane) to afford 6-(prop-1-en-2-yl)imidazo[1,5-a]pyridine (300 mg, 74%) as brown oil. LCMS R_(T)=0.26 min; m/z=158.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.26 min, ESI+ found [M+H]=158.8

Step 2: 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

A mixture of 6-(prop-1-en-2-yl)imidazo[1,5-a]pyridine (300 mg, 1.9 mmol) and 10% palladium on carbon (202 mg, 0.2 mmol) in methanol (30 mL) was hydrogenated (50 psi) at 20° C. for 72 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (10% methanol in dichloromethane) to afford 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (150 mg, 48%) as brown oil, used in the next step without further purification.

Step 3: ethyl 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

To a solution of 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (300 mg, 1.8 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (2.5 M, 1.1 mL, 2.7 mmol) at −78° C. Stirring at −78° C. was continued for 1 h, then ethyl chloroformate (1300 mg, 12.3 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched by addition of saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% dichloromethane) to afford ethyl 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (100 mg, 23%) as brown oil, used in the next step without further purification.

Step 4: 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylic acid

A mixture of 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (100 mg, 0.45 mmol) and potassium hydroxide (252 mg, 4.5 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH=4 by addition of hydrochloric acid (2.0 M). The mixture was concentrated under reduced pressure to afford crude 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylic acid (80 mg, 85%) as a white solid, used in the next step without further purification.

Step 5: 6-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide

A mixture of (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (40 mg, 0.2 mmol), 6-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylic acid (43 mg, 0.2 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (42 mg, 0.3 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (59 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. After evaporation of the solvent under reduced pressure, the residue was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonia hydroxide in water) to afford 6-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide (10 mg, 14%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=8.0 Hz, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.35-7.26 (m, 2H), 7.25-7.21 (m, 1H), 6.81 (s, 1H), 4.83-4.75 (m, 1H), 4.63-4.51 (m, 2H), 4.43-4.37 (m, 1H), 3.69-3.62 (m, 1H), 3.31 (s, 3H), 2.95-2.87 (m, 1H), 2.67-2.58 (m, 1H), 1.93-1.85 (m, 1H), 1.68-1.54 (m, 2H), 1.41-1.28 (m, 1H), 0.92-0.88 (m, 6H). LCMS R_(T)=0.84 min; m/z=393.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.84 min, ESI+ found [M+H]=393.1

Example 174 WX Method FF

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxamide

Step 1: 8-methylene-1,4-dioxaspiro[4.5]decane

To a suspension of (bromomethyl)triphenylphosphonium (34.12 g, 96.04 mmol) in tetrahydrofuran (200 mL) was added potassium tert-butoxide (10.8 g, 96.0 mmol) portionwise at 0° C. The resulting mixture was stirred at 0° C. for 1 h and then a solution of 1,4-dioxaspiro[4.5]decan-8-one (5.0 g, 32.0 mmol) in tetrahydrofuran (20 mL) was added dropwise. After addition, the reaction mixture was slowly warmed to 23° C. and stirred for 18 h. The reaction mixture was quenched by addition of water (120 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to afford 8-methylene-1,4-dioxaspiro[4.5]decane (3.9 g, 79%) as yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 4.67 (s, 2H), 3.98 (s, 4H), 2.37-2.30 (m, 4H), 1.73-1.70 (m, 4H).

Step 2: Spiro[2.5]octan-6-one

To a solution of 8-methylene-1,4-dioxaspiro[4.5]decane (3.9 g, 25.3 mmol) in toluene (7.2 mL) was added diethylzinc (1.0 M, 63.2 mL, 63.2 mmol) at −40° C. The mixture was stirred for 10 min and then diiodomethane (33.9 g, 126.4 mmol) added dropwise. After addition, the resulting mixture was allowed to warm to 24° C. and stirred for 18 h. The reaction mixture was poured onto ice-cooled saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) affording a colorless oil. A mixture of this oil and trifluoroacetic acid (2.9 mL, 38.9 mmol) in tetrahydrofuran (8 mL) and water (7 mL) was stirred at 23° C. for 2 h. The mixture was adjusted to pH=7 by addition of aqueous sodium hydroxide (2 M) and extracted with diethyl ether (3×30 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure affording crude spiro[2.5]octan-6-one (1.4 g, 44.6% over 2 steps) as colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 2.40 (t, J=6.8 Hz, 4H), 1.67 (t, J=6.4 Hz, 4H), 0.47 (s, 4H).

Step 3: Ethyl 2-oxo-2-(6-oxospiro[2.5]octan-7-yl)acetate

To a solution of spiro[2.5]octan-6-one (500 mg, 4.03 mmol) in ethanol (5 mL) was added sodium ethanoxide and diethyl oxalate (588 mg, 4.0 mmol) at 0° C. After addition, the mixture was allowed to warm to 20° C. and stirred for 20 h. The solvent was removed under reduced pressure affording crude ethyl 2-oxo-2-(6-oxospiro[2.5]octan-7-yl)acetate (800 mg, 88%) as a yellow solid, used as is in the next step without further purification.

Step 4: Ethyl spiro[1,3a,4,6,7,7a-hexahydroindazole-5,1′-cyclopropane]-3-carboxylate

To a solution of ethyl 2-oxo-2-(6-oxospiro[2.5]octan-7-yl)acetate (800 mg, 3.57 mmol) in glacial acetic acid (3 mL) was added hydrazine (0.12 mL, 3.92 mmol) at 0° C. The mixture was stirred for 18 h at 23° C. and then extracted with ethyl acetate (3×30 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) affording ethyl spiro[1,3a, 1,4,6,7-tetrahydroindazole-5,1′-cyclopropane]-3-carboxylate (50 mg, 6.4%) as a pale yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 4.41-4.30 (m, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.62 (s, 2H), 1.62 (t, J=6.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H), 0.44 (s, 4H).

LCMS R_(T)=0.817 min; m/z=220.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.817 min, ESI+ found [M+H]=220.9.

Step 5: Spiro[1,3a,4,6,7,7a-hexahydroindazole-5,1′-cyclopropane]-3-carboxylic acid

A mixture of ethyl spiro[1,3a, 1,4,6,7-tetrahydroindazole-5,1′-cyclopropane]-3-carboxylate (50 mg, 0.23 mmol) and lithium hydroxide hydrate (27 mg, 1.13 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 23° C. for 18 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The solution was then extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure affording crude spiro[1,3a, 1,4,6,7-tetrahydro indazole-5,1′-cyclopropane]-3-carboxylic acid (40 mg, 91%) as a white solid: LCMS R_(T)=1.456 min; m/z=193.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.04% formic acid over 3 mins) retention time 1.456 min, ESI+ found [M+H]=193.2.

Step 6 (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxamide

A mixture of spiro[1,3a, 1,4,6,7-tetrahydroindazole-5,1′-cyclopropane]-3-carboxylic acid (40 mg, 0.21 mmol), (3s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (44 mg, 0.23 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (33 mg, 0.25 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (45 mg, 0.25 mmol) in N, N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 38-68%/0.05% ammonia in water) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxamide (18.7 mg, 24%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.48 (d, J=6.0 Hz, 1H), 7.37-7.16 (m, 3H), 4.85-4.75 (m, 1H), 4.53-4.44 (m, 1H), 4.42-4.35 (m, 1H), 3.31 (s, 3H), 2.63 (t, J=5.6 Hz, 2H), 2.41 (s, 2H), 1.49 (t, J=5.6 Hz, 2H), 0.46-0.20 (m, 4H). LCMS R_(T)=0.856 min; m/z=367.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.856 min, ESI+ found [M+H]=367.1.

Example 175 WX Method RRRRRR

5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of (5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (22 mg, 0.11 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (20 mg, 0.11 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (14-24% methanol in water and 0.05% ammonia hydroxide) to afford 5-benzyl-N-(9-methyl-8-oxo-6,7, 8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-4H-1,2,4-triazole-3-carboxamide (5 mg, 12%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.34-7.22 (m, 5H), 7.09 (s, 1H), 6.96 (s, 1H), 4.53-4.48 (m, 1H), 4.32-4.26 (m, 1H), 4.16 (s, 2H), 4.10-4.02 (m, 1H), 3.38 (s, 3H), 2.77-2.90 (m, 1H), 2.29-2.21 (m, 1H). LCMS R_(T)=1.21 min; m/z=366.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.21 min, ESI+ found [M+H]=366.1.

Example 176 WX Method SSSSSS

(5S)—N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

A mixture of (5S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (26 mg, 0.11 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (20 mg, 0.11 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (17-47% methanol in water and 0.05% ammonia hydroxide) to afford (5S)—N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-5-(trifluoro methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (10.7 mg, 24%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.09 (d, J=1.2 Hz, 1H), 6.96 (d, J=1.2 Hz, 1H), 4.52-4.47 (m, 1H), 4.32-4.26 (m, 1H), 4.07-4.05 (m, 1H), 3.39 (s, 3H), 3.14-3.10 (m, 1H), 2.88-2.84 (m, 2H), 2.76-2.70 (m, 1H), 2.64-2.48 (m, 2H), 2.21-2.20 (m, 2H), 1.74-1.69 (m, 1H). LCMS R_(T)=0.69 min; m/z=397.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.69 min, ESI+ found [M+H]=397.0.

Example 177 WX Method TTTTTT

1-(3,4-difluorobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-pyrazole-3-carboxamide

A mixture of 1-[(3,4-difluorophenyl)methyl]pyrazole-3-carboxylic acid (26 mg, 0.11 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (20 mg, 0.11 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (30-40% methanol in water and 0.05% ammonia hydroxide) to afford 1-(3,4-difluorobenzyl)-N-(9-methyl-8-oxo-6,7, 8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-pyrazole-3-carboxamide (10.8 mg, 24%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.75 (d, J=2.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.09-7.01 (m, 2H), 6.95 (d, J=1.2 Hz, 1H), 6.75-6.74 (m, 1H), 5.38 (s, 2H), 4.53-4.48 (m, 1H), 4.31-4.26 (m, 1H), 4.06-4.03 (m, 1H), 3.38 (s, 3H) 2.85-2.79 (m, 1H), 2.29-2.23 (m, 1H). LCMS R_(T)=1.99 min; m/z=401.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3 mins) retention time 1.99 min, ESI+ found [M+H]=401.1.

Example 178 WX Method UUUUUU

1-(3,4-difluorobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-imidazole-4-carboxamide

A mixture of 1-[(3,4-difluorophenyl)methyl]imidazole-4-carboxylic acid (26 mg, 0.11 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (20 mg, 0.11 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13-43% methanol in water and 0.05% ammonia hydroxide) to afford 1-(3,4-difluorobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-imidazole-4-carboxamide (13.1 mg, 29%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.78 (s, 1H), 7.67 (s, 1H), 7.28-7.23 (m, 2H), 7.11-7.08 (m, 2H), 6.94 (d, J=1.6 Hz, 1H), 5.23 (s, 2H), 4.50-4.46 (m, 1H), 4.31-4.26 (m, 1H), 4.07-4.02 (m, 1H), 3.38 (s, 3H), 2.86-2.80 (m, 1H), 2.25-2.19 (m, 1H).

LCMS R_(T)=1.85 min; m/z=401.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.85 min, ESI+ found [M+H]=401.1.

Example 179 WX Method DDDDDD

(S)-5-benzyl-N-(1-isopropyl-4-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: 1-isopropyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (10.0 g, 88.4 mmol) in N, N-dimethylformamide (50 mL) was added potassium carbonate (36.7 g, 265.3 mmol) and stirred at 25° C. for 1 h, then 2-iodopropane (17.6 mL, 176.9 mmol) was added. The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1-isopropyl-4-nitro-pyrazole (11.0 g, 80%) as yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.09 (s, 1H), 4.61-4.54 (m, 1H), 1.52 (d, J=6.4 Hz, 6H).

Step 2: 5-chloro-1-isopropyl-4-nitro-1H-pyrazole

To a cooled (−78° C.) solution of 1-isopropyl-4-nitro-pyrazole (5.0 g, 32.2 mmol) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl)azanide (1.0 M, 34.9 mL, 34.9 mmol) dropwise. The mixture was stirred at −78° C. for 30 min and then hexachloroethane (8.36 g, 35.3 mmol) was added. The mixture was stirred at 25° C. for 18 h and quenched by addition of saturated aqueous ammonium chloride (80 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 5-chloro-1-isopropyl-4-nitro-pyrazole (5.0 g, 82%) as colorless solid: ¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 4.85-4.80 (m, 1H), 1.49 (d, J=6.8 Hz, 6H).

Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-((1-isopropyl-4-nitro-1H-pyrazol-5-yl)oxy)propanoic acid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (4.38 g, 21.4 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (1.1 g, 28.5 mmol, 60%) at 0° C. The mixture was stirred at 0° C. for 1 h. At which time 5-chloro-1-isopropyl-4-nitro-pyrazole (2.7 g, 14.2 mmol) was added. After addition, the mixture was stirred at 20° C. for another 3 h, and then quenched by addition of water (30 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica (0-100% ethyl acetate in petroleum ether) to afford (S)-2-((tert-butoxycarbonyl)amino)-3-((1-isopropyl-4-nitro-1H-pyrazol-5-yl) oxy)propanoic acid (0.7 g, 14%) as yellow oil: LCMS R_(T)=0.68 min; m/z=302.9 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.68 min, ESI+ found [M−55]=302.9.

Step 4: (S)-3-((4-amino-1-isopropyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid

A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-((1-isopropyl-4-nitro-1H-pyrazol-5-yl)oxy)propanoic acid (0.2 g, 0.56 mmol) and 10% palladium on carbon (59 mg, 0.06 mmol) in methanol (20 mL) was hydrogenated (50 psi) at 25° C. for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford (S)-3-((4-amino-1-isopropyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (180 mg, 98%) as black oil: LCMS R_(T)=0.558 min; m/z=328.9 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.558 min, ESI+ found [M+H]=328.9.

Step 5: (S)-tert-butyl(1-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate

To a solution of (S)-3-((4-amino-1-isopropyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (540 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL) was added N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (378 mg, 1.97 mmol). The reaction mixture was stirred at 25° C. for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford (S)-tert-butyl (1-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (170 mg, 33%) as brown solid: LCMS R_(T)=0.79 min; m/z=254.9 (M−56)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.79 min, ESI+ found [M−56]⁺=254.9.

Step 6: (S)-tert-butyl(1-isopropyl-4-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate

To a solution of (S)-tert-butyl (1-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (170 mg, 0.55 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (151 mg, 1.10 mmol) and iodomethane (94 mg, 0.66 mmol). The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford (S)-tert-butyl (1-isopropyl-4-methyl-5-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (120 mg, 68%) as green oil. LCMS R_(T)=0.69 min; m/z=268.9 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.69 min, ESI+ found [M−56]⁺=268.9.

Step 7: (S)-6-amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one

A mixture of (S)-tert-butyl (1-isopropyl-4-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (100 mg, 0.31 mmol) and hydrochloric acid (4 M in EtOAc, 5.0 mL, 20.0 mmol) in ethyl acetate (5 mL) was stirred at 25° C. for 2 h. The reaction mixture was adjusted pH=8 by addition of ammonia hydroxide and then concentrated under reduced pressure to give crude (S)-6-amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one (69 mg, 100%) as white solid, used in the next step without further purification.

Step 8: (S)-5-benzyl-N-(1-isopropyl-4-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one (13 mg, 0.06 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (12 mg, 0.06 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (9 mg, 0.07 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (13 mg, 0.07 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 0-40%/0.1% ammonium hydroxide in water) to afford (S)-5-benzyl-N-(1-isopropyl-4-methyl-5-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (7 mg, 28%) as white solids: ¹H NMR (400 MHz, CD₃OD) δ 7.48 (s, 1H), 7.35-7.21 (m, 5H), 4.67-4.64 (m, 1H), 4.60-4.53 (m, 2H), 4.45-4.40 (m, 1H), 4.18 (s, 2H), 3.37 (s, 3H), 1.45-1.40 (m, 6H). LCMS R_(T)=0.99 min; m/z=410.3 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.03% trifluoroacetic over 2 mins) retention time 0.99 min, ESI+ found [M+H]=410.3.

Example 180 WX Method FFFFFF

(S)-1-(3,4-difluorobenzyl)-N-(1-isopropyl-4-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-imidazole-4-carboxamide

A mixture of (S)-6-amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one (17 mg, 0.08 mmol), 1-[(3,4-difluorophenyl)methyl]pyrazole-3-carboxylic acid (19 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (13 mg, 0.09 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (17 mg, 0.09 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 0-40%/0.1% ammonium hydroxide in water) to afford (S)-1-(3,4-difluorobenzyl)-N-(1-isopropyl-4-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-b][1,4]oxazepin-6-yl)-1H-imidazole-4-carboxamide (13 mg, 39%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.78 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.29-7.18 (m, 2H), 7.12-7.10 (m, 1H), 6.80 (d, J=2.4 Hz, 1H), 5.39 (s, 2H), 4.67-4.53 (m, 3H), 4.44-4.39 (m, 1H), 3.37 (s, 3H), 1.46-1.40 (m, 6H). LCMS R_(T) 1.117 min; m/z=445.3 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.03% trifluoroacetic over 2 mins) retention time 1.117 min, ESI+ found [M+H]⁺=445.3.

Example 181 WX Method IIIIII

(S)-5-benzyl-N-(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-1,4-dimethyl-6,7-dihydropyrazolo[3,4-b][1,4]oxazepin-5-one (24 mg, 0.12 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (25 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (19 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to afford (S)-5-benzyl-N-(1,4-dimethyl-5-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide: ¹H NMR (400 MHz, CD₃OD) δ 7.69 (s, 1H), 7.38-7.31 (m, 5H), 4.98-4.93 (m, 1H), 4.72-4.69 (m, 1H), 4.58-4.53 (m, 1H), 4.34 (s, 2H), 3.72 (s, 3H), 3.37 (s, 3H). LCMS R_(T)=0.74 min; m/z=382.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.74 min, ESI+ found [M+H]=382.1.

Example 182 WX Method JJJJJJ

(S)-1-(3,4-difluorobenzyl)-N-(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-pyrazole-3-carboxamide

A mixture of (S)-6-amino-1,4-dimethyl-6,7-dihydropyrazolo[3,4-b][1,4]oxazepin-5-one (24 mg, 0.12 mmol), 1-[(3,4-difluorophenyl)methyl]pyrazole-3-carboxylic acid (32 mg, 0.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (19 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N,N³-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to afford (S)-1-(3,4-difluorobenzyl)-N-(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-pyrazole-3-carboxamide (14 mg, 27%) as a light yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.79 (s, 1H), 7.65 (s, 1H), 7.26-7.21 (m, 2H), 7.12-7.10 (m, 1H), 6.79 (d, J=2.0 Hz, 1H), 5.39 (s, 2H), 4.81-4.78 (m, 1H), 4.68-4.65 (m, 1H), 4.50-4.45 (m, 1H), 3.71 (s, 3H), 3.37 (s, 3H). LCMS R_(T)=0.80 min; m/z=417.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=417.1.

Example 183 WX Method KKKKKK

(S)-1-(3,4-difluorobenzyl)-N-(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-imidazole-4-carboxamide

A mixture of (S)-6-amino-1,4-dimethyl-6,7-dihydropyrazolo[3,4-b][1,4]oxazepin-5-one (24 mg, 0.12 mmol), 1-[(3,4-difluorophenyl)methyl]imidazole-4-carboxylic acid (32 mg, 0.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (19 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to afford (S)-1-(3,4-difluorobenzyl)-N-(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-imidazole-4-carboxamide (16 mg, 32%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 8.24 (s, 1H), 7.62 (s, 1H), 7.52-7.50 (m, 1H), 7.40-7.35 (m, 2H), 5.50 (d, J=6.0 Hz, 2H), 5.00-4.93 (m, 1H), 4.65-4.57 (m, 2H), 3.70 (s, 3H), 3.35 (s, 3H). LCMS R_(T)=0.74 min; m/z=417.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.74 min, ESI+ found [M+H]=417.0.

Examples 184 and 185 Unsubstituted Acid from Method K & WX Method C

(R)-1-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide and (S)-1-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

Step 1: Ethyl 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

To a solution of ethyl 5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (600 mg, 2.3 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (474 mg, 3.4 mmol) and iodoethane (426 mg, 2.8 mmol). The mixture was stirred at 25° C. for 15 h and quenched by addition of ice water (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to afford ethyl 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (300 mg, 45%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 4.37-4.31 (m, 1H), 4.16-4.10 (m, 1H), 3.32-3.29 (m, 1H), 2.96-2.93 (m, 1H), 2.78-2.50 (m, 3H), 2.34-2.23 (m, 1H), 1.78-1.73 (m, 1H), 1.40 (q, J 7.2 Hz, 6H).

Step 2: 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

A mixture of ethyl 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (388 mg, 1.3 mmol) and potassium hydroxide (375 mg, 6.7 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure. The residue was dissolved in water (10 mL) and adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (263 mg, 75%) as white solids: LCMS R_(T)=1.13 min; m/z=263.0 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.1% formic acid over 2.0 mins) retention time 1.13 min, ESI+ found [M+H]=263.0.

Step 3: (R)-1-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide and (S)-1-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

To a solution of 1-ethyl-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (263 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL) was added methyl (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (193 mg, 1.0 mmol), (E)-3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (8 mg, 0.04 mmol) and 1-benzo[d][1,2,3]triazol-1-ol (385 mg, 2.0 mmol). The resulting solution was stirred at 25° C. for 13 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (48-78% acetonitrile in water and 0.05% FA) to afford 1-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (360 mg, 82.2%) as white solid.

The above racemate was separated by chiral SFC to give:

Peak 1 (retention time 0.545 min, 96.0% ee, arbitrarily assigned R configuration) (61 mg, 16.9%): ¹H NMR (400 MHz, CD₃OD) δ 7.46-7.41 (m, 1H), 7.35-7.23 (m, 3H), 4.96-4.89 (m, 1H), 4.62-4.56 (m, 1H), 4.39-4.36 (m, 1H), 4.12-4.08 (m, 2H), 3.41 (s, 3H), 3.11-3.06 (m, 1H), 2.92-2.86 (m, 1H), 2.72-2.46 (m, 3H), 2.23-2.13 (m, 1H), 1.74-1.71 (m, 1H), 1.41 (t, J=7.2 Hz, 3H). LCMS R_(T)=0.84 min; m/z=437.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 1.5 mins) retention time 0.84 min, ESI+ found [M+H]=437.2.

Peak 2 (retention time 0.908 min, 93.0% ee, arbitrarily assigned S configuration) (55 mg, 13.5%): ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.41 (m, 1H), 7.32-7.23 (m, 3H), 4.97-4.93 (m, 1H), 4.60-4.55 (m, 1H), 4.37-4.32 (m, 1H), 4.11-4.07 (m, 2H), 3.41 (s, 3H), 3.12-3.07 (m, 1H), 2.84-2.78 (m, 1H), 2.72-2.41 (m, 3H), 2.27-2.15 (m, 1H), 1.73-1.70 (m, 1H), 1.40 (t, J=7.2 Hz, 3H). LCMS R_(T)=0.84 min; m/z=437.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 1.5 mins) retention time 0.84 min, ESI+ found [M+H]=437.2.

Example 186 WX Method BB

5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

Step 1: 2-ethyltetrahydro-2H-pyran-4-ol

A mixture of propionaldehyde (5.0 g, 86.0 mmol) and but-3-en-1-ol (6.2 g, 86.0 mmol) in 20% sulfuric acid (100 mL) was stirred at 80° C. for 12 h. The mixture was cooled and then adjusted to pH=9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20 to 30% ethyl acetate in petroleum ether) to afford 2-ethyltetrahydro-2H-pyran-4-ol (10.0 g, 91%) as light yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 4.03-3.98 (m, 1H), 3.80-3.72 (m, 1H), 3.42-3.35 (m, 1H), 3.21-3.14 (m, 1H), 1.98-1.93 (m, 1H), 1.90-1.84 (m, 2H), 1.63-1.42 (m, 3H), 1.22-1.13 (m, 1H), 0.93 (t, J=7.6 Hz, 3H).

Step 2: 2-ethyldihydro-2H-pyran-4(3H)-one

To a solution of 2-ethyltetrahydro-2H-pyran-4-ol (10.0 g, 76.8 mmol) in dichloromethane (50 mL) was added pyridiniumchlorochromate (22.7 g, 105.6 mmol) portionwise over 5 min. The reaction was stirred for 18 h at 25° C. and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 2-ethyldihydro-2H-pyran-4(3H)-one (8.3 g, 84%) as light yellow oil, used in the next step as is: ¹H NMR (400 MHz, CDCl₃) δ 4.30-4.25 (m, 1H), 3.73-3.61 (m, 1H), 3.52-3.46 (m, 1H), 2.62-2.53 (m, 1H), 2.42-2.23 (m, 3H), 1.72-1.62 (m, 1H), 1.60-1.50 (m, 1H), 0.96 (t, J=7.6 Hz, 3H)

Step 3: ethyl 5-ethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a solution of 2-ethyldihydro-2H-pyran-4(3H)-one (4.5 g, 35.1 mmol) was added pyrrolidine (125 mg, 1.75 mmol) and ethyl diazoacetate (2.0 g, 17.5 mmol). The mixture was stirred for 15 h at 25° C. and then diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford ethyl 5-ethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (640 mg, 16%) as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 4.94 (d, J=14.8 Hz, 1H), 4.71 (d, J=14.4, 1H), 4.42-4.36 (m, 2H), 3.51-3.45 (m, 1H), 2.94-2.89 (m, 1H), 2.61-2.54 (m, 1H), 1.78-1.66 (m, 2H), 1.41-1.38 (m, 3H), 1.07-1.03 (m, 3H).

Step 4: 5-ethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid

A mixture of ethyl 5-ethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (50 mg, 0.22 mmol) and lithium hydroxide hydrate (94 mg, 2.23 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to afford crude 5-ethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (40 mg, 91.4%) as a light yellow solid, used in next step without further purification.

Step 5: 5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (43 mg, 0.22 mmol), 5-ethyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (40 mg, 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (47 mg, 0.24 mmol) and 1-hydroxybenzotriazole (33 mg, 0.24 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 24-54 with 0.05% ammonia hydroxide in water) to afford 5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (9 mg, 11%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.40 (m, 1H), 7.30-7.28 (m, 2H), 7.24-7.21 (m, 1H), 5.00-4.94 (m, 1H), 4.82-4.67 (m, 1H), 4.60-4.58 (m, 2H), 4.36-4.35 (m, 1H), 3.42-3.41 (m, 4H), 2.85-2.80 (m, 1H), 2.52-2.32 (m, 1H), 1.70-1.60 (m, 2H), 1.01 (t, J=7.2 Hz, 3H). LCMS R_(T)=1.03 min; m/z=371.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.03 min, ESI+ found [M+H]=371.2.

Example 187 WX Method F

5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

Step 1: methyl 2-(4-methylpyridin-2-yl)acetate

A mixture of methyl 2-(4-bromo-2-pyridyl)acetate (600 mg, 2.6 mmol), potassium carbonate (721 mg, 5.2 mmol), trimethylboroxine (982 mg, 7.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.04 mmol) in 1,4-dioxane (5 mL) was heated to 120° C. for 4 h under nitrogen. After cooled, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate) to afford methyl 2-(4-methylpyridin-2-yl)acetate (350 mg, 81%) as brown oil, used in the next step without further purification.

Step 2: methyl 5-methyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate

To a solution of methyl 2-(4-methylpyridin-2-yl)acetate (300 mg, 1.82 mmol) in acetonitrile (10 mL) was added 4-acetamidobenzenesulfonyl azide (436 mg, 1.82 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (415 mg, 2.72 mmol) at 0° C. The resulting mixture was stirred at 20° C. for 2 h and then concentrated under reduced pressure. The residue was purified with preparative TLC (50% ethyl acetate in petroleum ether) to afford methyl 5-methyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (200 mg, 57%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=6.8 Hz, 1H), 8.05 (s, 1H), 6.98 (d, J=6.8 Hz, 1H), 4.05 (s, 3H), 2.54 (s, 3H).

Step 3: methyl 5-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate

A mixture of methyl 5-methyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (200 mg, 1.0 mmol) and 10% palladium on carbon (111 mg, 0.1 mmol) in methanol (5 mL) was hydrogenated (50 psi) at 25° C. for 48 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude methyl 5-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (200 mg, 98%) as a brown solid: LCMS R_(T)=1.22 min; m/z=196.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide over 3.0 mins) retention time 1.22 min, ESI+ found [M+H]=196.1

Step 4: 5-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylic acid

A mixture of methyl 5-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (100 mg, 0.51 mmol) and potassium hydroxide (287 mg, 5.1 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH=4 by addition of hydrochloric acid (2.0 M). The solution was concentrated under reduced pressure to afford crude 5-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylic acid (80 mg, 86%) as a white solid, used in the next step without further purification.

Step 6: 5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (40 mg, 0.21 mmol), 5-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylic acid (38 mg, 0.21 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (42 mg, 0.31 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (59 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (60 to 90% acetonitrile in water and 0.05% ammonium hydroxide) affording 5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide (20 mg, 27%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.42-8.39 (m, 1H), 7.51-7.47 (m, 1H), 7.33-7.26 (m, 2H), 7.25-7.21 (m, 1H), 4.88-4.81 (m, 1H), 4.65-4.57 (m, 1H), 4.55-4.47 (m, 1H), 4.42-4.36 (m, 1H), 4.24-4.20 (m, 1H), 3.31 (s, 3H), 3.15-3.07 (m, 1H), 2.44-2.31 (m, 2H), 2.01-1.95 (m, 1H), 1.72-1.63 (m, 1H), 1.04 (d, J=6.4 Hz, 3H). LCMS R_(T)=0.81 min; m/z=356.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.81 min, ESI+ found [M+H]=356.1.

Example 188 WX Method HHHHHH

(S)—N—((S)-1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

Step 1: 1-methyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (10.0 g, 88.4 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (36.67 g, 265.3 mmol) and iodomethane (25.1 g, 176.8 mmol). The mixture and stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1-methyl-4-nitro-1H-pyrazole (10.0 g, 89%) as yellow solid, used next step without further purification.

Step 2: 5-chloro-1-methyl-4-nitro-1H-pyrazole

To a cooled (−78° C.) solution of 1-methyl-4-nitro-1H-pyrazole (5.0 g, 39.4 mmol) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl)azanide (1.0 M, 39.4 mL, 39.4 mmol) dropwise. The mixture was stirred at −78° C. for 30 mins, and hexachloroethane (11.1 g, 47.2 mmol) was added. After addition, the mixture was stirred at 25° C. for 18 h and then quenched by addition of saturated aqueous ammonium chloride (80 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 5-chloro-1-methyl-4-nitro-1H-pyrazole (5.0 g, 79%) as white solid, used in the next step as is.

Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-((1-methyl-4-nitro-H-pyrazol-5-yl)oxy)propanoic acid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (3.1 g, 14.9 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.2 g, 29.7 mmol, 60%) at 0° C. The mixture was stirred at 0° C. for 1 h and then added 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.0 g, 12.4 mmol). Stirring at 20° C. was continued for 3 h, and the reaction mixture was quenched by addition of hydrochloric acid (2.0 M, 30 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford (S)-2-((tert-butoxycarbonyl)amino)-3-((1-methyl-4-nitro-1H-pyrazol-5-yl)oxy)propanoic acid (0.6 g, 15%) as yellow oil. LCMS R_(T)=0.77 min; m/z=352.9 (M+Na)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.77 min, ESI+ found [M+Na]⁺=352.9.

Step 4: (S)-3-((4-amino-1-methyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid

A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-((1-methyl-4-nitro-1H-pyrazol-5-yl)oxy)propanoic acid (600 mg, 1.82 mmol) and 10% palladium on carbon (193 mg, 0.18 mmol) in methanol (50 mL) was hydrogenated (50 psi) at 20° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford (S)-3-((4-amino-1-methyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (500 mg, 92%) as yellow oil: LCMS R_(T)=0.523 min; m/z=301.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.523 min, ESI+ found [M+H]⁺=301.1.

Step 5: (S)-tert-butyl(1-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate

To a solution of (S)-3-((4-amino-1-methyl-1H-pyrazol-5-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.5 g, 1.66 mmol) in N,N-dimethylformamide (10 mL) was added N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (383 mg, 2.00 mmol). The reaction mixture was stirred at 20° C. for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford (S)-tert-butyl(1-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (200 mg, 43%) as yellow oil.

Step 6: (S)-tert-butyl(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate

To a solution of (S)-tert-butyl (1-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (0.2 g, 0.71 mmol) in N,N-dimethylformamide (10 mL) was added iodomethane (121 mg, 0.85 mmol) and potassium carbonate (196 mg, 1.42 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford (S)-tert-butyl(1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)carbamate (200 mg, 95%) as yellow oil. LCMS R_(T)=0.61 min; m/z=226.8 (M−56)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.61 min, ESI+ found [M−56]⁺=226.8.

Step 7: (S)-6-amino-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one

A mixture of (S)-tert-butyl (1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]ox azepin-6-yl)carbamate (200 mg, 0.67 mmol) and hydrochloric acid (4 M in EtOAc, 2 mL, 8 mmol) in ethyl acetate (5 mL) was stirred at 20° C. for 2 h. The reaction mixture was adjusted to pH=8 by addition of ammonia hydroxide. The mixture was then concentrated under reduced pressure to afford (S)-6-amino-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one (130 mg, 101%) as yellow solid, used in the next step without further purification.

Step 8: (S)—N—((S)-1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

A mixture of (S)-6-amino-1,4-dimethyl-6,7-dihydropyrazolo[3,4-b][1,4]oxazepin-5-one (24 mg, 0.12 mmol), (5S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (32 mg, 0.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (19 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13 to 43% methyl alcohol in water and 0.05% hydrochloric acid) to afford (S)—N—((S)-1,4-dimethyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-5-(t rifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide (10 mg, 20%) as a light yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.65 (s, 1H), 5.06-4.95 (m, 1H), 4.68-4.65 (m, 1H), 4.49-4.44 (m, 1H), 3.72 (s, 3H), 3.37 (s, 3H), 3.20-3.15 (m, 1H), 2.94-2.84 (m, 1H), 2.79-2.49 (m, 3H), 2.27-2.18 (m, 1H), 1.82-1.67 (m, 1H). LCMS R_(T)=0.79 min; m/z=413.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=413.0.

Example 189 WX Method S

2,2-difluoro-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxamide

Step 1: 1,1-difluorospiro[2.5]octan-6-one

To a mixture of 8-methylene-1,4-dioxaspiro[4.5]decane (1.2 g, 7.8 mmol), sodium fluoride (33 mg, 0.78 mmol) in xylene (5 mL) was added a solution of trimethylsilyl2,2-difluoro-2-(fluorosulfonyl)acetate (4.9 g, 19.5 mmol) in xylene (4 mL) dropwise over a period 1 h at 120° C. After addition, the mixture was stirred for an additional 1 h and then cooled to 20° C. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford a yellow oil. The material was diluted with tetrahydrofuran (30 mL) and added hydrochloric acid (35%, 3 mL). The resulting mixture was stirred at 20° C. for 16 h and then adjusted to pH=7 by addition of saturated aqueous sodium bicarbonate. The solution was then extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 1,1-difluorospiro[2.5]octan-6-one (300 mg, 24.2% over 2 steps) as colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 2.51-2.39 (m, 4H), 2.01-1.95 (m, 4H), 1.26 (t, J=8.4 Hz, 2H).

Step 2: ethyl 2-(1,1-difluoro-6-oxospiro[2.5]octan-5-yl)-2-oxoacetate

To a solution of 1,1-difluorospiro[2.5]octan-6-one (300 mg, 1.87 mmol) in ethanol (15 mL) was added sodium ethanoxide (140 mg, 2.06 mmol) and diethyl oxalate (274 mg, 1.87 mmol) at 0° C. After addition, the mixture was allowed to warm to 20° C. for 20 h. The solution was concentrated under reduced pressure to afford crude ethyl 2-(1,1-difluoro-6-oxospiro[2.5]octan-5-yl)-2-oxoacetate (480 mg, 99%) as a yellow solid, used in the next step without further purification.

Step 3: ethyl 2,2-difluoro-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxylate

To a solution of ethyl 2-(1,1-difluoro-6-oxospiro[2.5]octan-5-yl)-2-oxoacetate (480 mg, 1.84 mmol) in acetic acid (5 mL) was added hydrazine hydrate (130 mg, 2.03 mmol, 50%) at 0° C. The reaction was stirred at 25° C. for 1 h and then quenched by addition of saturated aqueous sodium bicarbonate. The mixture was extracted with methanol/dichloromethane (1:10) (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl 2,2-difluoro-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxylate (150 mg, 32%) as yellow oil: LCMS R_(T)=0.688 min; m/z=256.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.688 min, ESI+ found [M+H]=256.8.

Step 4: 2,2-difluoro-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxylic acid

A mixture of ethyl 2,2-difluoro-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxylate (150 mg, 0.59 mmol) and lithium hydroxide hydrate (140 mg, 5.85 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred for 20 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 2,2-difluoro-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxylic acid (50 mg, 37%) as a white solid, used in the next step without further purification.

Step 5: 2,2-difluoro-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxamide

A mixture of 2,2-difluoro-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxylic acid (50 mg, 0.22 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (36 mg, 0.26 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (46 mg, 0.24 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (50 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (34-64% acetonitrile in water and 0.05% hydrochloric acid) to afford 2,2-difluoro-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-indazole]-3′-carboxamide (37 mg, 41%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.32-7.28 (m, 2H), 7.24-7.22 (m, 1H), 4.85-4.80 (m, 1H), 4.51-4.47 (m, 1H), 4.42-4.38 (m, 1H), 3.31 (s, 3H), 2.79-2.74 (m, 1H), 2.70-2.67 (m, 2H), 2.59-2.55 (m, 1H), 1.80-1.78 (m, 2H), 1.38-1.32 (m, 1H), 1.28-1.23 (m, 1H). LCMS R_(T)=0.836 min; m/z=403.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.836 min, ESI+ found [M+H]=403.1.

Example 190 was prepared according to WX Method B (see Example 171 above). Data is provided in Table 2.

Example 191 WX Method GG

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

Step 1: Methyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate

A mixture of 1-oxido-4-(trifluoromethyl)pyridin-1-ium (500 mg, 3.1 mmol), N, N-diisopropylethylamine (1.2 g, 9.2 mmol), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (1.1 g, 6.1 mmol) and bromo[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate (1.6 g, 3.4 mmol) in tetrahydrofuran (15 mL) was heated at 45° C. for 2 h and then poured into water (20 mL). The resulting solution was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford crude methyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate (485 mg, 72%) as yellow oil: LCMS R_(T)=0.633 min; m/z=219.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.633 min, ESI+ found [M+H]=219.9.

Step 2: Methyl 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylate

To a solution of methyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate (480 mg, 2.19 mmol) in acetonitrile (12 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 3.29 mmol) and 4-acetamidobenzenesulfonylazide (526 mg, 2.19 mmol) at 0° C. The resulting mixture was allowed to warm to 25° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford methyl 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylate (380 mg, 71%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.53 (d, J=7.2 Hz, 1H), 8.48 (s, 1H), 7.71-7.68 (m, 1H), 3.98 (s, 3H). LCMS R_(T)=0.749 min; m/z=245.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.749 min, ESI+ found [M+H]=245.9.

Step 3: 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylic acid

A mixture of methyl 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylate (75 mg, 0.31 mmol) and lithium hydroxide hydrate (36 mg, 1.53 mmol) in tetrahydrofuran (5 mL) was stirred at 23° C. for 18 h. The organic solvent was evaporated under reduced pressure, and the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure affording crude 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylic acid (40 mg, 57%) as a white solid, used in the next step without further purification.

Step 4: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

A mixture of 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylic acid (40 mg, 0.17 mmol), (3 s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (37 mg, 0.19 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (28 mg, 0.21 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (40 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 39-69%/0.05% ammonia in water) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1, 2,3]triazolo[1,5-a]pyridine-3-carboxamide (37.3 mg, 53%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (d, J=7.6 Hz, 1H), 9.01 (d, J=8.0 Hz, 1H), 8.43 (s, 1H), 7.67-7.61 (m, 1H), 7.56-7.49 (m, 1H), 7.38-7.22 (m, 3H), 5.00-4.91 (m, 1H), 4.77-4.70 (m, 1H), 4.48-4.43 (m, 1H), 3.33 (s, 3H). LCMS R_(T)=0.861 min; m/z=406.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.861 min, ESI+ found [M+H]=406.0.

Example 192 WX Method HH

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

Step 1: Methyl 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylate

A mixture of methyl 5-(trifluoromethyl)triazolo[1,5-a]pyridine-3-carboxylate (150 mg, 0.61 mmol) and 10% palladium on carbon (65 mg, 0.06 mmol) in methanol (5 mL) was hydrogenated (50 psi) at 25° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure affording crude methyl 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylate (82 mg, 54%) as yellow oil: LCMS R_(T)=0.704 min; m/z=249.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.704 min, ESI+ found [M+H]=249.9.

Step 2: 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid

A mixture of methyl 5-(trifluoromethyl)-4, 5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylate (82 mg, 0.33 mmol) and lithium hydroxide hydrate (39 mg, 1.65 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 23° C. for 18 h. After evaporated of the organic solvent, the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure affording crude 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid (60 mg, 77%) as a white solid, used in the next step without further purification.

Step 3: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

A mixture of 5-(trifluoromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid (60 mg, 0.26 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (41 mg, 0.31 mmol), (3s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (54 mg, 0.28 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (59 mg, 0.31 mmol) in N, N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 33-63%/0.05% ammonia in water) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-4, 5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide (45.8 mg, 44%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.56-8.49 (m, 1H), 7.53-7.46 (m, 1H), 7.40-7.15 (m, 3H), 4.91-4.80 (m, 1H), 4.68-4.60 (m, 2H), 4.44-4.23 (m, 2H), 3.31 (s, 3H), 3.15-3.02 (m, 1H), 2.89-2.79 (m, 1H), 2.53-2.51 (m, 1H), 2.34-2.26 (m, 1H), 2.13-1.99 (m, 1H).

LCMS R_(T)=0.833 min; m/z=410.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.833 min, ESI+ found [M+H]=410.0.

Example 193 WX Method L

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(trifluoromethyl) imidazo[1,5-a]pyrimidine-8-carboxamide

Step 1: ethyl 2-((diphenylmethylene)amino)-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate

A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (2.0 g, 11.0 mmol), potassium carbonate (2.3 g, 16.4 mmol), tetrabutylammonium bromide (1.8 g, 5.5 mmol) and ethyln-(diphenylmethylene)glycinate (1.5 g, 5.5 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was heated at 100° C. for 12 h. After cooled, the reaction mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with water (3×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford ethyl 2-(benzhydrylideneamino)-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate (1.9 g, 42%) as yellow oil: LCMS R_(T)=0.90 min; m/z=414.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.90 min ESI+ found [M+H]=414.1.

Step 2: ethyl 2-amino-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate hydrochloride

To a solution of ethyl 2-(benzhydrylideneamino)-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate (200 mg, 0.48 mmol) in dichloromethane (10 mL) was slowly added hydrochloric acid (1.0 M, 12 mL, 12 mmol). The reaction mixture was stirred for 3 h at 25° C. and the layers were separated. The aqueous layer was washed with dichloromethane (2×20 mL) and then concentrated under reduced pressure to afford crude ethyl 2-amino-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate hydrochloride (100 mg, 83%) as a light yellow solid: LCMS R_(T)=0.41 min; m/z=250.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.41 min, ESI+ found [M+H]=250.1.

Step 3: ethyl 2-formamido-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate

Formic acid (98%, 0.8 mL) was added to acetic anhydride (2 mL) at 0° C. The resulting solution was stirred 4 h at 50° C. This anhydride solution was slowly added into a solution of ethyl 2-amino-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate hydrochloride (100 mg, 0.40 mmol) in tetrahydrofuran (5 mL) at 0° C. After addition, stirring was continued for another 6 h. The reaction mixture was quenched by addition of water (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (4×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% methanol in dichloromethane) to afford ethyl 2-formamido-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate (70 mg, 63%) as a light yellow solid: LCMS R_(T)=0.63 min; m/z=278.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.63 min, ESI+ found [M+H]=278.1.

Step 4: ethyl 2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate

A solution of ethyl 2-formamido-2-(4-(trifluoromethyl)pyrimidin-2-yl)acetate (70 mg, 0.25 mmol) in phosphoryl trichloride (2 mL) was heated at 115° C. for 12 h under nitrogen. After cooled, the reaction mixture was poured onto ice water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (2×30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford ethyl 2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (55 mg, 84%) as a pale yellow solid: LCMS R_(T)=1.78 min; m/z=260.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoroacetic acid over 7.0 mins) retention time 1.78 min, ESI+ found [M+H]=260.1.

Step 5: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(trifluoromethyl) imidazo[1,5-a]pyrimidine-8-carboxamide

To a mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (40 mg, 0.21 mmol) and ethyl 2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (54 mg, 0.21 mmol) in tetrahydrofuran (20 mL) was added trimethylaluminum (2.0 M, 0.62 mL, 1.25 mmol) dropwise under nitrogen atmosphere. The mixture was stirred at 75° C. for 15 h, cooled and then quenched by addition of saturated aqueous potassium sodium tartrate (10 mL). The resulting mixture was stirred at 25° C. for 1 h and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% ammonia hydroxide in water) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxamide (14 mg, 16%) as yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (d, J=6.8 Hz, 1H), 8.68 (s, 1H), 8.38 (d, J=7.2 Hz, 1H), 7.52-7.50 (m, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.36-7.25 (m, 3H), 4.95-4.88 (m, 1H), 4.55-4.44 (m, 2H), 3.34 (s, 3H). LCMS R_(T)=1.233 min; m/z=406.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.233 min, ESI+ found [M+H]=406.1.

Example 194 was prepared according to Method GG (see Example 35). Data is provided in Table 2.

Example 195 WX Method VVVVVV

1-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (41 mg, 0.20 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (30 mg, 0.17 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (45 mg, 0.25 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (34 mg, 0.25 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonium in water) to afford 1-benzyl-N-(9-methyl-8-oxo-6,7, 8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide (26.6 mg, 42%) as colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.56 (d, J=7.6 Hz, 1H), 7.39-7.30 (m, 5H), 7.13 (s, 1H), 6.88 (s, 1H), 5.48 (s, 2H), 4.32-4.22 (m, 2H), 3.95-3.90 (m, 1H), 3.25 (s, 3H), 2.67-2.65 (m, 1H), 2.39-2.33 (m, 1H). LCMS R_(T)=1.36 min; m/z=366.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.36 min, ESI+ found [M+H]=366.1.

Example 196 WX Method WWWWWW

1-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-benzyltriazole-4-carboxylic acid (41 mg, 0.20 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (30 mg, 0.17 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (45 mg, 0.25 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (34 mg, 0.25 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonium in water) to afford 1-benzyl-N-(9-methyl-8-oxo-6,7, 8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,3-triazole-4-carboxamide (12 mg, 19%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.66 (s, 1H), 7.38-7.33 (m, 5H), 7.12 (s, 1H), 6.88 (s, 1H), 5.65 (s, 2H), 4.32-4.23 (m, 2H), 3.94-3.90 (m, 1H), 3.25 (s, 3H), 2.67 (s, 1H), 2.37-2.33 (m, 1H). LCMS R_(T)=1.425 min; m/z=366.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.425 min, ESI+ found [M+H]=366.1.

Example 197 WX Method GGGGGG

(S)-5-benzyl-N-(1-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b][1,4]oxazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one (15 mg, 0.07 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (15 mg, 0.07 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (13 mg, 0.09 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (17 mg, 0.09 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 12-42%/0.05% ammonia hydroxide in water) to afford (S)-5-benzyl-N-(1-isopropyl-5-oxo-4,5,6,7-tetrahydro-H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (8 mg, 28%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.34-7.26 (m, 5H), 7.25-7.20 (m, 1H), 4.87-4.68 (m, 1H), 4.67-4.64 (m, 1H), 4.55-4.51 (m, 1H), 4.41-4.36 (m, 1H), 4.18 (s, 2H), 1.41 (d, J=7.2 Hz, 6H). LCMS R_(T)=0.93 min; m/z=396.2 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 0.93/min, ESI+ found [M+H]=396.2

Example 198 WX Method YYYYYY

1-benzyl-N-(6-oxo-4,5,6,7,8,9-hexahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-7-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (40 mg, 0.20 mmol), 7-amino-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (40 mg, 0.19 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25-55/0.05% ammonia hydroxide in water) to afford 1-benzyl-N-(6-oxo-4,5,6,7,8,9-hexahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-7-yl)-1H-1,2, 4-triazole-3-carboxamide (24 mg, 31%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.71 (d, J=6.8 Hz, 1H), 7.40-7.31 (m, 5H), 7.27 (s, 1H), 5.50 (s, 2H), 4.76 (t, J=8.0 Hz, 1H), 4.41-4.29 (m, 4H), 3.96 (t, J=8.0 Hz, 1H), 3.32-3.28 (m, 1H), 2.50-2.27 (m, 2H).

LCMS R_(T)=1.09 min; m/z=394.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.09 min, ESI+ found [M+H]=394.2.

Example 199 WX Method XXXXXX

5-benzyl-N-(6-oxo-4,5,6,7,8,9-hexahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-7-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: 4-benzylmorpholin-3-one

To a solution of morpholin-3-one (10.0 g, 98.9 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (3.96 g, 98.9 mmol, 60%). The reaction mixture was stirred at 0° C. for 0.5 h and then benzyl bromide (16.9 g, 98.9 mmol) was added. The reaction mixture was stirred at 20° C. for 15 h and then poured on to ice water (100 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 75% ethyl acetate in petroleum ether) to afford 4-benzylmorpholin-3-one (10.0 g, 53%) as a colorless oil, used in the next step as is.

Step 2: 7-benzyl-1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]oxazine

N,N-dimethylformamide (9.9 g, 135.4 mmol) was added dropwise to a solution of phosphoryl trichloride (16.8 g, 110.0 mmol) in 1,2-dichloroethane (40 mL) at 0° C. The mixture was allowed stirring for 10 min and then 4-benzylmorpholin-3-one (7.0 g, 36.6 mmol) in of 1,2-dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 min, at 25° C. for 3 h and at 45° C. for 1 h. The solvent was removed under reduced pressure and the residue was diluted with ethanol (80 mL). The solution was cooled to 0° C. and added hydrazine hydrate (18.3 g, 366.0 mmol, 85%) dropwise. After addition, the mixture was stirred for 1 h at −5° C., for 2 h at 25° C. and for 15 h at 60° C. to give emerged gradually dissolved and a clear, deep red colored solution. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 7-benzyl-1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]oxazine (3.0 g, 38%) as a white solid: LCMS R_(T)=0.84 min; m/z=216.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.84 min, ESI+ found [M+H]=216.2.

Step 3: 1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]oxazine

To a solution of 7-benzyl-1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]oxazine (3.0 g, 13.9 mmol) in 2-propanol (50 mL) were added 10% palladium on carbon (5.93 g, 5.57 mmol). The reaction mixture was stirred at 20° C. under the atmosphere of hydrogen (15 psi) for 15 h and then filtered. The filtrate was concentrated under reduced pressure to afford 1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]oxazine (1.7 g, 98%) as a yellow oil, used in the next step without further purification.

Step 4: 4-chloro-1-(5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)butan-1-one

A solution of 1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]oxazine (1.8 g, 14.4 mmol) in 4-chlorobutanoyl chloride (10.1 g, 71.9 mmol) was stirred at 50° C. for 1 h. The reaction mixture was quenched by slow addition of methanol (20 mL) and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) afford 4-chloro-1-(5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)butan-1-one (3.0 g, 91%) as a yellow solid: LCMS R_(T)=0.86 min; m/z=230.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.86 min, ESI+ found [M+H]=230.2.

Step 5: 4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one

To a solution of 4-chloro-1-(5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)butan-1-one (500 mg, 2.18 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.4 g, 4.35 mmol). The reaction mixture was stirred at 25° C. for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (300 mg, 71%) as a white solid: LCMS R_(T)=0.83 min; m/z=194.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.83 min, ESI+ found [M+H]=194.1.

Step 6: 7-iodo-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one

To a solution of 4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (100 mg, 0.52 mmol) in dichloromethane (10 mL) was treated with iodotrimethylsilane (621 mg, 3.11 mmol) and N,N,N²,N²-tetramethylethane-1,2-diamine(360 mg, 3.11 mmol) at −15° C. The mixture was stirred at −15° C. for 1.5 h, then iodine (394 mg, 1.55 mmol) was added in one portion. After addition, the mixture was stirred at −15° C. for 2 h and then quenched by addition of saturated aqueous sodium sulfite (5%, 40 mL). The mixture was extracted with dichloromethane (3×40 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 7-iodo-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (80 mg, 48%) as a light yellow solid, used as is in the next step.

Step 7: 7-azido-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one

To a solution of 7-iodo-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (50 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) were added sodium azide (14 mg, 0.21 mmol). The reaction mixture was stirred at 25° C. for 2 h and then poured into ice water (5 mL). The solution was extracted with dichloromethane (2×10 mL). The combined organic layers were concentrated under reduced pressure to afford 7-azido-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (36 mg, 98%) as a light yellow oil: LCMS R_(T)=1.39 min; m/z=235.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.39 min, ESI+ found [M+H]=235.1.

Step 8: 7-amino-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one

A mixture of 7-azido-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (36 mg, 0.15 mmol) and 10% palladium on carbon (164 mg, 0.15 mmol) in methanol (10 mL) was hydrogenated (15 psi) at 25° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 7-amino-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (30 mg, 94%) as a black oil, used in the next step without further purification.

5-benzyl-N-(6-oxo-4,5,6,7,8,9-hexahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-7-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (40 mg, 0.20 mmol), 7-amino-4,5,8,9-tetrahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-6(7H)-one (40 mg, 0.19 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 10-40/0.05% ammonia hydroxide in water) to afford 5-benzyl-N-(6-oxo-4,5,6,7,8,9-hexahydro-3-oxa-1,5a,9a-triazabenzo[cd]azulen-7-yl)-4H-1,2, 4-triazole-3-carboxamide (13.9 mg, 18%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 14.48 (br. s, 1H), 8.75 (s, 1H), 7.36-7.22 (m, 6H), 4.80-4.72 (m, 1H), 4.39-4.24 (m, 4H), 4.13 (s, 2H), 4.00-3.92 (m, 1H), 3.30-3.27 (m, 1H), 2.50-2.27 (m, 2H). LCMS R_(T)=1.09 min; m/z=394.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.09 min, ESI+ found [M+H]=394.2.

Example 200 WX Method T

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxamide

Step 1: 2-hydrazinyl-5-(trifluoromethyl)pyrazine

A mixture of 2-chloro-5-(trifluoromethyl)pyrazine (2.0 g, 11.0 mmol) in ethanol (20 mL) was added hydrazine hydrate (50%, 2.2 g, 21.9 mmol). The mixture was stirred at 45° C. for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 2-hydrazinyl-5-(trifluoromethyl)pyrazine (1.2 g, 62%) as a yellow solid: LCMS R_(T)=1.393 min; m/z=179.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% formic acid over 3 mins) retention time 1.393 min, ESI+ found [M+H]=179.1.

Step 2: ethyl 2-oxo-2-(2-(5-(trifluoromethyl)pyrazin-2-yl)hydrazinyl)acetate

To a solution of 2-hydrazinyl-5-(trifluoromethyl)pyrazine (1.1 g, 6.2 mmol) and triethylamine (937 mg, 9.26 mmol) in dichloromethane (20 mL) was added ethyl oxalyl chloride (1.0 g, 7.4 mmol) at 0° C. The mixture was stirred at 25° C. for 20 h and then quenched by addition of water (30 mL). The resulting mixture was extracted with dichloromethane (3×35 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford ethyl 2-oxo-2-(2-(5-(trifluoromethyl)pyrazin-2-yl)hydrazinyl)acetate (1.5 g, 87%) as a dark yellow solid: LCMS R_(T)=1.511 min; m/z=279.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% formic acid over 3 mins) retention time 1.511 min, ESI+ found [M+H]=279.1.

Step 3: ethyl 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate

A mixture of ethyl 2-oxo-2-(2-(5-(trifluoromethyl)pyrazin-2-yl)hydrazinyl)acetate (1.0 g, 3.6 mmol) and p-toluenesulfonicacid (310 mg, 1.8 mmol) in toluene (20 mL) was heated at 115° C. for 20 h. After cooled, the solution was diluted with water (20 mL) and extracted with dichloromethane (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude ethyl 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (600 mg, 64%) as a red solid:

LCMS R_(T)=0.613 min; m/z=261.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.613 min, ESI+ found [M+H]=261.1.

Step 4: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxamide

To a mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol) and ethyl 6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (61 mg, 0.23 mmol) in tetrahydrofuran (3 mL) was added trimethylaluminum (2.0 M, 0.78 mL, 1.56 mmol). The mixture was stirred at 50° C. for 15 h and then quenched by addition of saturated aqueous potassium sodium tartrate (10 mL). Stirring was continued for 1 h and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (30-60% acetonitrile in water and 0.05% ammonium hydroxide) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6-(trifluoromethyl)-[1, 2,4]triazolo[4,3-a]pyrazine-3-carboxamide (16 mg, 17%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.67 (s, 1H), 9.31 (s, 1H), 7.55-7.52 (m, 1H), 7.35-7.26 (m, 3H), 4.96-4.92 (m, 1H), 4.81-4.74 (m, 1H), 4.49-4.44 (m, 1H), 3.33 (s, 3H). LCMS R_(T)=0.830 min; m/z=407.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.830 min, ESI+ found [M+H]=407.0.

Example 201 WX Method Y

5-ethyl-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5, 7-dihydrofuro[3,4-c]pyridazine-3-carboxamide

Step 1: 3-chloro-5-ethyl-5-methylfuro[3,4-c]pyridazin-7(5H)-one

To a solution of 6-chloropyridazine-3-carboxylic acid (2.5 g, 15.8 mmol) in tetrahydrofuran (100 mL) was added lithium diisopropylazanide (2.0 M, 19.7 mL, 39.4 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and then butan-2-one (10.2 g, 141.9 mmol) was added. The reaction mixture was warmed up to 25° C. and stirred for 16 h and then quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 3-chloro-5-ethyl-5-methylfuro[3,4-c]pyridazin-7(5H)-one (300 mg, 9%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H), 2.16-2.08 (m, 1H), 2.02-1.96 (m, 1H), 1.73 (s, 3H), 0.87 (t, J=7.6 Hz, 3H).

Step 2: 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazin-7-ol

To a solution of 3-chloro-5-ethyl-5-methylfuro[3,4-c]pyridazin-7(5H)-one (300 mg, 1.41 mmol) in toluene (15 mL) was added diisobutylaluminum hydride (1.0 M, 2.82 mL, 2.82 mmol) dropwise at −70° C. After addition, stirring at −70° C. was continued for 2 h and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazin-7-ol (250 mg, 83%) as yellow oil, used as is in the next step.

Step 3: 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine

To a solution of 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazin-7-ol (250 mg, 1.16 mmol) in dichloromethane (20 mL) was added boron trifluoride diethyl etherate (826 mg, 5.82 mmol) at 0° C. Stirring was continued for 30 min at 0° C., and then triethyl silane (677 mg, 5.82 mmol) was added. The mixture was stirred for additional 3 h at 25° C. and then quenched by addition of saturated aqueous sodium bicarbonate. The resulting solution was extracted with dichloromethane (3×20 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to afford 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine (100 mg, 43%) as yellow oil, used as is in the next step.

Step 4: methyl 5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxylate

A mixture of 3-chloro-5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine (100 mg, 0.50 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (37 mg, 0.05 mmol) and triethylamine (255 mg, 2.52 mmol) in methanol (20 mL) was heated at 80° C. for 4 h under carbon oxide (40 psi). The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl 5-ethyl-5-methyl-5,7-dihydrofuro [3,4-c]pyridazine-3-carboxylate (80 mg, 72%) as yellow oil, used as is in the next step.

Step 5: 5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxylic acid

A mixture of methyl 5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxylate (80 mg, 0.36 mmol) and lithium hydroxide hydrate (75.6 mg, 1.8 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25° C. for 2 h. After evaporation of the organic solvent under reduced pressure, the aqueous layer was acidified to pH=5 by addition of hydrochloric acid (1.0 M) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxylic acid (60 mg, 80%) as colorless oil, used as is in the next step.

Step 6: 5-ethyl-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxamide

A mixture of 5-ethyl-5-methyl-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxylic acid (60 mg, 0.29 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (66 mg, 0.34 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (66 mg, 0.34 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (46 mg, 0.34 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% HCl in water) to afford 5-ethyl-5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-c]pyridazine-3-carboxamide (44.4 mg, 40%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (d, J=4.4 Hz, 1H), 8.14 (s, 1H), 7.52 (d, J=6.8 Hz, 1H), 7.34-7.25 (m, 3H), 5.26 (s, 2H), 4.97-4.92 (m, 1H), 4.72-4.67 (m, 1H), 4.51-4.46 (m, 1H), 3.34 (s, 3H), 1.90-1.78 (s, 2H), 1.46 (s, 3H), 0.74-0.71 (m, 3H). LCMS R_(T)=0.831 min; m/z=383.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.831 min, ESI+ found [M+H]⁺=383.1.

Example 202 WX Method II

(S)-1-ethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

Step 1: Methyl 1-ethylpyrazolo[4,3-c]pyridine-6-carboxylate

To a solution of methyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate (300 mg, 1.70 mmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (702 mg, 5.06 mmol) and iodoethane (528 mg, 3.39 mmol). The reaction mixture was stirred at 45° C. for 30 min and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 7-37/0.05% ammonia in water) to give:

Methyl 1-ethylpyrazolo[4,3-c]pyridine-6-carboxylate (175 mg, 55%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 4.60-4.54 (m, 2H), 3.91 (s, 3H), 1.41 (t, J=7.6 Hz, 3H). LCMS R_(T)=1.185 min; m/z=206.1 (M+H)⁺.

Methyl 2-ethylpyrazolo[4,3-c]pyridine-6-carboxylate (110 mg, 35%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.83 (s, 1H), 8.29 (s, 1H), 4.61-4.54 (m, 2H), 3.88 (s, 3H). 1.54 (t, J=7.6 Hz, 3H). LCMS R_(T)=1.242 min; m/z=206.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.04% formic acid over 3 mins) retention time 1.185 min, ESI+ found [M+H]=206.1, 1.242 min, ESI+ found [M+H]=206.1

Step 2: 1-ethylpyrazolo[4,3-c]pyridine-6-carboxylic acid

A mixture of methyl 1-ethylpyrazolo[4,3-c]pyridine-6-carboxylate (50 mg, 0.24 mmol) and lithium hydroxide hydrate (29 mg, 1.22 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 25° C. for 18 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure affording crude 1-ethylpyrazolo[4,3-c]pyridine-6-carboxylic acid (40 mg, 86%) as a white solid, used in the next step without further purification.

Step 3: (S)-1-ethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

A mixture of 1-ethylpyrazolo[4,3-c]pyridine-6-carboxylic acid (40 mg, 0.21 mmol), (3 s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (44 mg, 0.23 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (34 mg, 0.25 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (48 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia in water) affording (S)-1-ethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide (29.9 mg, 39.0%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 1H), 9.03 (d, J=8.0 Hz, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.57-7.47 (m, 1H), 7.41-7.23 (m, 3H), 4.97-4.88 (m, 1H), 4.61-4.49 (m, 4H), 3.34 (s, 3H), 1.39 (t, J=7.2 Hz, 3H). LCMS R_(T)=0.812 min; m/z=366.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.812 min, ESI+ found [M+H]=366.1.

Example 203 WX Method EEEEEE

(S)-1-benzyl-N-(1-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[3,4-b][1,4]oxazepin-5(4H)-one (27 mg, 0.13 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (27 mg, 0.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (30 mg, 0.15 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 0-40%/0.1% ammonium hydroxide in water) to afford (S)-1-benzyl-N-(1-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b][1,4]oxazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (7 mg, 14%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.37 (s, 5H), 7.20 (s, 1H), 5.49 (s, 2H), 4.83 (s, 1H), 4.67-4.64 (m, 1H), 4.56-4.48 (m, 1H), 4.40-4.36 (m, 1H), 1.43-1.40 (m, 6H). LCMS R_(T)=0.958 min; m/z=396.2 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.03% trifluoroacetic over 2 mins) retention time 0.958 min, ESI+ found [M+H]⁺=396.2.

Example 204 WX Method LLLLLL

benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1, 2,4-triazole-3-carboxamide

Step 1: ethyl 4-(5-nitro-1H-imidazol-1-yl)butanoate

A mixture of 5-nitro-1H-imidazole (60.0 g, 530.0 mmol), ethyl 4-bromobutyrate (109.0 g, 557.0 mmol) and potassium carbonate (146.0 g, 1.1 mol) in N,N-dimethylformamide (300 mL) was heated to 120° C. for 2 h. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give ethyl 4-(5-nitro-1H-imidazol-1-yl)butanoate (7.0 g, 6%) as a colorless oil, used in the next step without further purification.

Step 2: ethyl 4-(5-amino-1H-imidazol-1-yl)butanoate

A mixture of ethyl 4-(5-nitro-1H-imidazol-1-yl)butanoate (7.0 g, 30.8 mmol) and 10% palladium on carbon (32.8 g, 30.8 mmol) in 1,4-dioxane (300 mL) was hydrogenated (15 psi) at 25° C. for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 4-(5-amino-1H-imidazol-1-yl)butanoate (4.0 g, 65%) as a brown oil:

LCMS R_(T)=1.25 min; m/z=198.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium hydroxide over 3.0 mins) retention time 1.25 min, ESI⁺ found [M+H]=198.2

Step 3: 4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of ethyl 4-(5-amino-1H-imidazol-1-yl)butanoate (500 mg, 2.5 mmol) in ethanol (20 mL) was added sodium ethanolate (863 mg, 12.7 mmol). The mixture was stirred at 25° C. for 4 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (200 mg, 52%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 7.48 (s, 1H), 6.53 (s, 1H), 4.04 (t, J=6.8 Hz, 2H), 2.23-2.18 (m, 2H), 2.15-2.07 (m, 2H).

Step 4: 1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (200 mg, 1.23 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (431 mg, 1.32 mmol) and iodomethane (175 mg, 1.23 mmol). The mixture was stirred at 25° C. for 3 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (100 mg, 46%) as a white solid, used as is in the next step.

Step 5: 3-iodo-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (100 mg, 0.61 mmol) in dichloromethane (10 mL) was added N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (946 mg, 7.26 mmol) and iodotrimethylsilane (1.45 g, 7.26 mmol) at −15° C. The mixture was stirred at −15° C. for 1.5 h, and then iodine (922 mg, 3.63 mmol) was added. Stirring was continued for 3 h and the reaction was quenched by addition of saturated aqueous solution sodium sulfite (5%, 5 mL). The solution was extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (100-200 mesh silica gel, 0 to 10% methanol in dichloromethane) to afford 3-iodo-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (10 mg, 6%) as a light yellow solid: LCMS R_(T)=1.34 min; m/z=292.0 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.34 min, ESI+ found [M+H]=292.0.

Step 6: 3-amino-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 3-iodo-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (10.0 mg, 0.03 mmol) in N,N-dimethylformamide (3 mL) was added ammonium hydroxide (0.01 mL, 0.34 mmol). The reaction mixture was stirred at 80° C. for 2 h and then concentrated under reduced pressure to afford 3-amino-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (6 mg, 97%) as a yellow oil, used in the next step without further purification.

Step 7: 1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (6.8 mg, 0.03 mmol), 3-amino-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (6.0 mg, 0.03 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (7.7 mg, 0.04 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (5.4 mg, 0.04 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 0-40/0.1% ammonium in water) to afford 1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (1.8 mg, 14%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.62 (s, 1H), 7.37-7.33 (m, 5H), 6.99 (s, 1H), 5.47 (s, 2H), 4.85-4.59 (m, 1H), 4.45-4.39 (m, 1H), 4.03-3.97 (m, 1H), 3.35 (s, 3H), 2.79-2.72 (m, 1H), 2.20-2.15 (m, 1H). LCMS R_(T)=1.67 min; m/z=366.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate 3 mins) retention time 1.67 min, ESI+ found [M+H]=366.1.

Example 205 WX Method I

5-(4-fluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

Step 1: 2-(4-fluorophenyl)tetrahydro-2H-pyran-4-ol

A mixture of 4-fluorobenzaldehyde (10.0 g, 86.0 mmol) and but-3-en-1-ol (11.6 g, 161.2 mmol) in 20% sulfuric acid (100 mL) was stirred at 80° C. for 12 h. The mixture was cooled and then adjusted to pH=9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20 to 30% ethyl acetate in petroleum ether) to afford 2-(4-fluorophenyl)tetrahydro-2H-pyran-4-ol (9.5 g, 56%) as light yellow oil, used in the next step without further purification.

Step 2: 2-(4-fluorophenyl)dihydro-2H-pyran-4(3H)-one

To a solution of 2-(4-fluorophenyl)tetrahydro-2H-pyran-4-ol (9.5 g, 48.4 mmol) in dichloromethane (50 mL) was added pyridiniumchlorochromate (12.0 g, 55.7 mmol) portionwise over 5 min. The reaction was stirred for 18 h at 25° C. and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 2-(4-fluorophenyl)dihydro-2H-pyran-4(3H)-one (7.2 g, 77%) as light yellow oil, used in the next step without further purification.

Step 3: ethyl 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a solution of 2-(4-fluorophenyl) dihydro-2H-pyran-4(3H)-one (2.00 g, 10.3 mmol) was added pyrrolidine (37 mg, 0.5 mmol) and ethyl diazoacetate (0.59 g, 5.2 mmol). The mixture was stirred for 15 h at 25° C. and then diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford ethyl 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (130 mg, 4%) as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.39 (m, 2H), 7.06 (t, J=8.6 Hz, 2H), 5.11-5.07 (m, 1H), 4.92-4.89 (m, 1H), 4.61-4.55 (m, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.17-3.13 (m, 1H), 2.93-2.86 (m, 1H), 1.34 (t, J=7.1 Hz, 3H).

Step 4: 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid

A mixture of ethyl 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (170 mg, 0.59 mmol) and lithium hydroxide hydrate (140 mg, 5.86 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to afford crude 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (70 mg, 46%) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.51-7.45 (m, 2H), 7.23-7.16 (m, 2H), 4.92-4.88 (m, 1H), 4.82-4.79 (m, 1H), 4.66-4.62 (m, 1H), 3.11-3.06 (m, 1H), 2.71-2.64 (m, 1H).

Step 5: 5-(4-fluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

A mixture of 5-(4-fluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (35 mg, 0.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (22 mg, 0.16 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (26 mg, 0.13 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (28 mg, 0.16 mmol) in N,N-dimethyformamide (3 mL) was stirred at 25° C. for 12 h. The reaction was concentrated to dryness under reduced pressure and the residue was purified by RP-HPLC (13 to 43% acetonitrile in water and 0.05% hydrochloric acid) to afford 5-(4-fluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (41 mg, 70%) as a light yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 7.48-7.38 (m, 3H), 7.30-7.28 (m, 3H), 7.09-7.06 (m, 2H), 4.98-4.93 (m, 2H), 4.88-4.83 (m, 1H), 4.61-4.58 (m, 2H), 4.57-4.33 (m, 1H), 3.40 (s, 3H), 3.13-3.08 (m, 1H), 2.80-2.74 (m, 1H). LCMS R_(T)=1.12 min; m/z=437.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.12 min, ESI+ found [M+H]⁺=437.2.

Example 206 WX Method J

5-(3,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

Step 1: 2-(3,4-difluorophenyl)tetrahydro-2H-pyran-4-ol

A mixture of 3,4-difluorobenzaldehyde (10.0 g, 70.4 mmol) and but-3-en-1-ol (5.1 g, 70.4 mmol) in 20% sulfuric acid (20 mL) was stirred at 80° C. for 12 h. The mixture was cooled and then adjusted to pH=9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 2-(3,4-difluorophenyl)tetrahydro-2H-pyran-4-ol (9.2 g, 61%) as pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.04 (m, 2H), 7.00 (s, 1H), 4.24-4.21 (m, 1H), 4.13-4.09 (m, 1H), 3.88-3.81 (m, 1H), 3.51 (t, J=12.0 Hz, 1H), 2.37 (br. s, 1H), 2.10-2.07 (m, H), 1.92-1.88 (m, 1H), 1.60-1.50 (m, 1H), 1.43-1.35 (m, 1H).

Step 2: 2-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one

To a solution of 2-(3,4-difluorophenyl)tetrahydro-2H-pyran-4-ol (9.2 g, 43.0 mmol) in dichloromethane (50 mL) was added pyridiniumchlorochromate (11.1 g, 51.5 mmol) portionwise over 5 min. The reaction was stirred for 18 h at 25° C. and then filtered. The filtrate was concentrated under reduced pressure. The crude was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) affording 2-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (6.5 g, 71%) as light yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.44 (m, 1H), 6.88 (t, J=8.0 Hz, 1H), 6.80-6.74 (m, 1H), 4.87-4.84 (m, 1H), 4.42-4.37 (m, 1H), 3.85-3.78 (m, 1H), 2.73-2.61 (m, 2H), 2.55-2.49 (m, 1H), 2.42-2.38 (m, 1H).

Step 3: ethyl 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a solution of 2-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (2.0 g, 9.4 mmol) in dimethyl sulfoxide (15 mL) was added pyrrolidine (34 mg, 0.5 mmol) and ethyl diazoacetate (538 mg, 4.7 mmol). The reaction was stirred for 16 h at 25° C. and then diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 35% ethyl acetate in petroleum ether) to afford ethyl 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (180 mg, 6%) as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.27 (m, 1H), 7.16-7.13 (m, 2H), 5.12-5.08 (m, 1H), 4.92-4.88 (m, 1H), 4.61-4.55 (m, 1H), 4.37 (q, J=7.6 Hz, 2H), 3.17-3.12 (m, 1H), 2.91-2.80 (m, 1H), 1.34 (t, J=7.6 Hz, 3H).

Step 4: 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid

A mixture of ethyl 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (180 mg, 0.58 mmol) and lithium hydroxide hydrate (139 mg, 5.80 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to afford crude 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (60 mg, 37%) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.58-7.45 (m, 2H), 7.36 (s, 1H), 5.00-4.96 (m, 1H), 4.88-4.85 (m, 1H), 4.72-4.70 (m, 1H), 3.18 (d, J=12.0 Hz, 1H), 2.75-2.68 (m, 1H).

Step 5: 5-(3,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (20 mg, 0.11 mmol), 5-(3,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (30 mg, 0.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.13 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (23 mg, 0.13 mmol) in N,N-dimethyformamide (3 mL) was stirred at 25° C. for 2 h. The reaction was concentrated to dryness under reduced pressure and the residue was purified by RP-HPLC (13 to 43% acetonitrile in water and 0.05% hydrochloric acid) to afford 5-(3,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (27 mg, 55%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.40-7.21 (m, 7H), 5.00-4.95 (m, 2H), 4.86-4.82 (m, 1H), 4.60-4.56 (m, 2H), 4.37-4.33 (m, 1H), 3.31 (s, 3H), 3.16-3.12 (m, 1H), 2.75-2.67 (m, 1H). LCMS R_(T)=1.15 min; m/z=455.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.15 min, ESI+ found [M+H]⁺=455.2.

Example 207 WX Method K

5-(2,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

Step 1: 2-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-ol

A mixture of 2,4-difluorobenzaldehyde (10.0 g, 70.4 mmol) and but-3-en-1-ol (5.1 g, 70.4 mmol) in 20% sulfuric acid (20 mL) was stirred at 80° C. for 12 h. The mixture was cooled and then adjusted to pH=9 by slow addition of 20% aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 2-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-ol (9.2 g, 61%) as pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.38 (m, 1H), 6.84 (t, J=8.4 Hz, 1H), 6.77-6.71 (m, 1H), 4.55 (d, J=11.0 Hz, 1H), 4.14-4.10 (m, 1H), 3.93-3.85 (m, 1H), 3.55 (t, J=12.0 Hz, 1H), 2.19 (br. s, 1H), 2.12 (m, 1H), 1.94-1.90 (m, 1H), 1.64-1.53 (m, 1H), 1.49-1.39 (m, 1H).

Step 2: 2-(2,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one

To a solution of 2-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-ol (5.0 g, 23.5 mmol) in dichloromethane (50 mL) was added pyridiniumchlorochromate (6.5 g, 28.0 mmol) portionwise over 5 min. The reaction was stirred for 18 h at 25° C. and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) affording 2-(2,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (3.3 g, 66%) as light yellow oil:

¹H NMR (400 MHz, CD₃OD) δ 7.24-7.09 (m, 2H), 7.04 (s, 1H), 4.59-4.56 (m, 1H), 4.42-4.37 (m, 1H), 3.83-3.76 (m, 1H), 2.72-2.59 (m, 2H), 2.54-2.38 (m, 2H).

Step 3: ethyl 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a solution of 2-(2,4-difluorophenyl) dihydro-2H-pyran-4(3H)-one (2.5 g, 11.8 mmol) in dimethyl sulfoxide (12 mL) was added pyrrolidine (84 mg, 1.2 mmol) and ethyl diazoacetate (1.3 g, 11.8 mmol). The mixture was stirred for 15 h at 25° C. and then diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (0 to 40% ethyl acetate in petroleum ether) to afford ethyl 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (185 mg, 5%) as light yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.50 (m, 1H), 6.92-6.88 (m, 1H), 6.83-6.78 (m, 1H), 5.11 (d, J=14.6 Hz, 1H), 4.93-4.85 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.19-3.14 (m, 1H), 2.88-2.81 (m, 1H), 1.34 (t, J=7.2 Hz, 3H).

Step 4: 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid

A mixture of ethyl 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (160 mg, 0.52 mmol) and lithium hydroxide hydrate (124 mg, 5.20 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred for 12 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to afford crude 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (75 mg, 52%) as a light yellow solid, used in the next step without further purification.

Step 5: 5-(2,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

A mixture of 5-(2,4-difluorophenyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (30 mg, 0.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.13 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (21 mg, 0.11 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (23 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 12 h. The reaction was concentrated to dryness under reduced pressure and the residue was purified by RP-HPLC (13 to 43% acetonitrile in water and 0.05% hydrochloric acid) to afford 5-(2,4-difluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (11 mg, 23%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.57-7.21 (m, 6H), 6.97-6.94 (m, 1H), 4.99-4.86 (m, 3H), 4.60-4.58 (m, 2H), 4.40-4.36 (m, 1H), 3.41 (s, 3H), 3.16-3.08 (m, 1H), 2.81-2.70 (m, 1H). LCMS R_(T)=1.14 min; m/z=455.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoroacetic acid over 2 mins) retention time 1.14 min, ESI+ found [M+H]⁺=455.2.

Example 208 WX Method RRRR

1-benzyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: N-(5-phenyl-1H-pyrazol-3-yl)formamide

A mixture of 5-phenyl-1H-pyrazol-3-amine (2.5 g, 15.7 mmol) and formic acid (10 mL, 15.71 mmol) was stirred at 110° C. in a sealed vessel for 2 h. The mixture was concentrated under reduced pressure and the residue was washed with water (50 mL) to give crude N-(5-phenyl-1H-pyrazol-3-yl)formamide (2.7 g, 92%) as a white solid: LCMS R_(T)=1.149 min; m/z=187.9 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.149 min, ESI+ found [M+H]=187.9.

Step 2: N-methyl-5-phenyl-1H-pyrazol-3-amine

To a solution of N-(5-phenyl-1H-pyrazol-3-yl)formamide (2.1 g, 11.2 mmol) in tetrahydrofuran (100 mL) was added borane (1.0 M, 45.0 mL, 45.0 mmol). The mixture was stirred at 0° C. in for 2 h and then quenched by addition of methanol (30 mL) and hydrochloric acid (10%, 5 mL). The resulting mixture was heated at 70° C. for 30 min, and then adjusted to pH=8 by addition of aqueous sodium hydroxide (10%). The mixture was then concentrated to dryness and the residue was taken up in ethyl acetate (100 mL), washed with water (2×50 mL), brine (50 mL), dried over magnesium sulfate and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give N-methyl-5-phenyl-1H-pyrazol-3-amine (1.9 g, 95%) as a white solid: LCMS R_(T)=0.52 min; m/z=173.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.52 min, ESI+ found [M+H]=173.8.

Step 3: 4-chloro-N-methyl-N-(5-phenyl-1H-pyrazol-3-yl)butanamide

A mixture of N-methyl-5-phenyl-1H-pyrazol-3-amine (1.9 g, 11.6 mmol) and 4-chlorobutanoyl chloride (5.2 mL, 46.2 mmol) was stirred at 60° C. for 16 h. The reaction was concentrated under reduce pressure. The residue was taken up in ethyl acetate (300 mL) and washed with water (100 mL) and brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 4-chloro-N-methyl-N-(5-phenyl-1H-pyrazol-3-yl)butanamide (2.3 g, 66%) as a white solid, use as is in the next step.

Step 4: 4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 4-chloro-N-methyl-N-(3-phenyl-1H-pyrazol-5-yl) butanamide (2.1 g, 7.6 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (4.9 g, 15.1 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.8 g, 96%) as a white solid: LCMS R_(T)=0.66 min; m/z=241.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.66 min, ESI+ found [M+H]=241.8.

Step 5: 6-iodo-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 4-methyl-2-phenyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.6 g, 6.6 mmol) in dry dichloromethane (20 mL) was added N¹,N¹,N³,N³-tetramethylpropane-1,3-diamine (10.4 g, 79.6 mmol) followed by iodotrimethylsilane (15.9 g, 79.6 mmol) at −15° C. The resulting solution was stirred 2 h at −15 OC and iodine (10 g, 39.80 mmol) was added in one portion. After stirred for 2 h at −15° C., the reaction mixture was quenched by addition of saturated sodium bisulfite (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 6-iodo-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.3 g, 55.0%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=1.6 Hz, 2H), 7.43-7.32 (m, 3H), 6.40 (s, 1H), 4.71-4.67 (m, 1H), 4.34-4.24 (m, 2H), 3.41 (s, 3H), 3.05-2.99 (m, 1H), 2.85-2.82 (m, 1H). LCMS R_(T)=0.71 min; m/z=367.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.71 min, ESI+ found [M+H]=367.8.

Step 6: 6-amino-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A solution of 6-iodo-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (550 mg, 1.5 mmol) and ammonia hydroxide (2 mL, 2.25 mmol, 36%) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 3% methanol in dichloromethane) to give 6-amino-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (200 mg, 52%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=2.0 Hz, 2H), 7.42-7.32 (m, 3H), 6.35 (s, 1H), 4.47-4.42 (m, 1H), 4.17-4.12 (m, 1H), 3.52-3.49 (m, 1H), 3.39 (s, 3H), 2.88-2.82 (m, 1H), 1.95-1.91 (m, 1H).

Step 7: 1-benzyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (24 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) and N,N-diisopropylethylamine (30 mg, 0.23 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (33% to 63% acetonitrile, 0.05% ammonia hydroxide in water) to give 1-benzyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (16 mg, 31%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.82 (d, J=7.2 Hz, 2H), 7.45-7.35 (m, 8H), 6.71 (s, 1H), 5.49 (s, 2H), 4.67-4.32 (m, 3H), 3.42 (s, 3H), 2.97-2.88 (m, 1H), 2.38-2.29 (m, 1H). LCMS R_(T)=0.71 min; m/z=442.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.71 min, ESI+ found [M+H]=442.0.

Example 209 WX Method SSSS

5-benzyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (24 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (27% to 57% acetonitrile, 0.05% ammonia hydroxide in water) to give 5-benzyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (4 mg, 7.3%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, J=6.8 Hz, 2H), 7.45-7.30 (m, 8H), 6.71 (s, 1H), 4.64-4.34 (m, 3H), 4.17 (s, 2H), 3.42 (s, 3H), 2.93-2.87 (m, 1H), 2.33-2.31 (m, 1H). LCMS R_(T)=0.69 min; m/z=442.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.69 min, ESI+ found [M+H]=442.0.

Example 210 WX Method H

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

Step 1: 2-(2,2,2-trifluoroethyl)tetrahydro-2H-pyran-4-ol

To a stirred mixture of 3,3,3-trifluoropropanal (5.0 g, 44.6 mmol) and 3-buten-1-ol (4.8 g, 66.9 mmol) was added 20% sulfuric acid (5 mL) at 0° C. The mixture was stirred at 80° C. for 3 h. After cooled, the mixture was adjusted to pH=9 by slow addition of NaHCO₃. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford the 2-(2,2,2-trifluoroethyl) tetrahydro-2H-pyran-4-ol (1.7 g, 20%) as yellow oil, used in the next step without further purification.

Step 2: 2-(2,2,2-trifluoroethyl)dihydro-2H-pyran-4(3H)-one

To a suspension of the 2-(2,2,2-trifluoroethyl)tetrahydro-2H-pyran-4-ol (200 mg, 1.1 mmol) and molecular sieves (4 Å) in dichloromethane (10 mL) was added pyridiniumchlorochromate (281 mg, 1.3 mmol) portionwise over 5 min. The mixture was stirred at 25° C. for 16 h and then filtered. The filtrate was concentrated under reduced pressure affording the crude product, which was purified by column chromatography (silica gel, 100-200 mesh, 10 to 20% ethyl acetate in petroleum ether) to afford 2-(2,2,2-trifluoroethyl)dihydro-2H-pyran-4(3H)-one as colorless oil (136 mg, 64%) as a brown oil, used in the next step without further purification.

Step 3: ethyl 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate

To a stirred solution of 2-(2,2,2-trifluoroethyl)dihydro-2H-pyran-4(3H)-one (100 mg, 0.55 mmol) in dimethyl sulfoxide (6 mL) was added pyrrolidine (6 mg, 0.08 mmol). The mixture was stirred at 20° C. for 15 min, then ethyl diazoacetate (125 mg, 1.1 mmol) was added. The mixture was stirred at 20° C. for 15 h and then poured into water (20 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10 to 30% ethyl acetate in petroleum ether) to afford ethyl 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate as a brown solid (50 mg, 31%): LCMS R_(T)=0.796 min; m/z=278.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.796 min, ESI+ found [M+H]=278.9.

Step 4: 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydro pyrano[3,4-c]pyrazole-3-carboxylic acid

A mixture of ethyl 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylate (50 mg, 0.18 mmol) and potassium hydroxide (20 mg, 0.36 mmol) in ethanol (8 mL) and water (2 mL) was stirred at 25° C. for 24 h. The reaction was concentrated to dryness under reduced pressure and the residue was adjusted to pH=2 by addition of hydrochloric acid (2.0 M). The solvent was removed, and the residue was dissolved in methanol (10 mL). The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure affording 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (40 mg, 88%) as a yellow solid: LCMS R_(T)=0.787 min; m/z=251.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.787 min, ESI+ found [M+H]=251.1.

Step 5: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

A mixture of N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (43 mg, 0.24 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.24 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (31 mg, 0.16 mmol), and 5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxylic acid (40 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated to dryness under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 46-76%/0.05% NH₄OH in water) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(2,2,2-trifluoroethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (6.2 mg, 9%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 13.06 (s, 1H), 8.05-8.02 (m, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.32-7.22 (m, 3H), 4.84 (m, 2H), 4.71-4.54 (m, 1H), 4.43-4.42 (m, 1H), 4.42-4.40 (m, 1H), 3.81 (s, 1H), 3.31 (s. 3H), 2.84-2.80 (m, 1H), 2.67-2.63 (m. 2H), 2.61-2.50 (m, 1H). LCMS R_(T)=1.063 min; m/z=425.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.063 min, ESI+ found [M+H]=425.2.

Example 211 WX Method M

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxamide

Step 1: 5-oxaspiro[3.5]nonan-8-yl methanesulfonate

To a mixture of cyclobutanone (6.0 g, 85.6 mmol) and 3-buten-1-ol (6.2 g, 85.6 mmol) was added methanesulfonic acid (17.3 g, 179.8 mmol). The mixture was stirred at 25° C. for 15 h and then adjusted to pH=9 by addition of saturated aqueous sodium bicarbonate. The resulting solution was extracted with dichloromethane (4×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate in petroleum ether) affording 5-oxaspiro[3.5]nonan-8-yl methanesulfonate (17.4 g, 92%) as yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 4.87-4.80 (m, 1H), 3.84-3.78 (m, 1H), 3.51-3.44 (m, 1H), 3.02 (s, 3H), 2.27-2.22 (m, 1H), 2.19-2.11 (m, 1H), 2.04-1.98 (m, 4H), 1.82-1.65 (m, 4H).

Step 2: 5-oxaspiro[3.5]nonan-8-ol

To a solution of 5-oxaspiro[3.5]nonan-8-yl methanesulfonate (22.0 g, 100 mmol) in tetrahydrofuran (180 mL) was added methylmagnesiumbromide (3.0 M, 50 mL, 150 mmol) at 0° C. After addition, the mixture was stirred at 25° C. for 20 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL). The resulting mixture was extracted with ethyl acetate (5×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20 to 30% ethyl acetate in petroleum ether) affording 5-oxaspiro[3.5]nonan-8-ol (12.9 g, 90%) as colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 3.84-3.75 (m, 2H), 3.45-3.38 (m, 1H), 2.19-2.10 (m, 2H), 2.00-1.90 (m, 4H), 1.85-1.73 (m, 2H), 1.70-1.58 (m, 1H), 1.52-1.35 (m, 2H).

Step 3: 5-oxaspiro[3.5]nonan-8-ol

To a solution of 5-oxaspiro[3.5]nonan-8-ol (12.9 g, 90.5 mmol) in dichloromethane (240 mL) was added pyridiniumchlorochromate (23.4 g, 108.6 mmol) portionwise over 5 min. The reaction was stirred for 16 h at 25° C. and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) affording 5-oxaspiro[3.5]nonan-8-one (11.5 g, 91%) as colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 3.87-3.84 (m, 2H), 2.54 (s, 2H), 2.39-2.36 (m, 2H), 2.17-2.09 (m, 2H), 1.98-1.92 (m, 2H), 1.82-1.74 (m, 1H), 1.67-1.55 (m, 1H).

Step 4: ethyl 4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxylate

To a stirred solution of 5-oxaspiro[3.5]nonan-8-one (4.9 g, 35.1 mmol) in dimethyl sulfoxide (40 mL) was added pyrrolidine (120 mg, 1.8 mmol), followed by ethyl diazoacetate (2.0 g, 17.5 mmol). The mixture was stirred at 25° C. for 15 h and then poured into water (60 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford ethyl 4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxylate (0.80 g, 19%) as brown oil. ¹H NMR (400 MHz, CDCl₃) δ 4.79 (s, 2H), 4.43-4.38 (m, 2H), 2.96 (s, 2H), 2.29-2.21 (m, 2H), 1.95-1.84 (m, 3H), 1.81-1.69 (m, 1H), 1.43-1.40 (m, 3H).

Step 5: 4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxylic acid

A mixture of ethyl 4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxylate (50 mg, 0.21 mmol) and lithium hydroxide hydrate (76 mg, 3.2 mmol)) in tetrahydrofuran (4 mL) and water (1 mL) was stirred for 20 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to afford crude 4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxylic acid (49 mg, 100%) as a white solid: LCMS R_(T)=0.539 min; m/z=208.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.539 min, ESI+ found [M+H]=208.8.

Step 6: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (30 mg, 0.16 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol), 4′,7′-dihydro-1′H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxylic acid (49 mg, 0.23 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4′,7′-dihydro-1 ¹H-spiro[cyclobutane-1,5′-pyrano[3,4-c]pyrazole]-3′-carboxamide (16.9 mg, 27%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.50-7.48 (m, 1H), 7.35-7.27 (m, 2H), 7.25-7.22 (m, 1H), 4.87-4.80 (m, 1H), 4.65 (s, 2H), 4.55-4.50 (m, 1H), 4.43-4.39 (m, 1H), 3.32 (s, 3H), 2.74 (s, 2H), 2.12-2.05 (m, 2H), 1.79-1.64 (m, 4H). LCMS R_(T)=1.021 min; m/z=383.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.021 min, ESI+ found [M+H]⁺=383.2.

Example 212 WX Method DDDDDD

5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide

A mixture of 5-methyl-5-phenyl-4,7-dihydro-1H-pyrano[3,4-c]pyrazole-3-carboxylic acid (42 mg, 0.16 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (31 mg, 0.16 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (44 mg, 0.33 mmol). Then N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (62 mg, 0.33 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 48-78 with 0.05% formic acid in water) to afford 5-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole-3-carboxamide (25 mg, 36%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.23 (m, 9H), 5.05-5.00 (m, 1H), 4.73-4.69 (m, 1H), 4.61-4.59 (m, 1H), 4.39-4.35 (m, 2H), 3.53-3.48 (m, 1H), 3.40 (s, 3H), 2.96-2.91 (m, 1H), 1.51 (s, 3H). LCMS R_(T)=3.37 min; m/z=433.4 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.1% formic acid over 7.0 mins) retention time 3.37 min, ESI+ found [M+H]=433.4.

Example 213 WX Method JJ

(S)-1-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

Step 1: Methyl 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylate

To a solution of methyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate (300 mg, 1.69 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (702 mg, 5.08 mmol) and 2-iodopropane (576 mg, 3.39 mmol). The reaction mixture was stirred at 45° C. for 3 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 12-42/0.05% ammonia in water) to give:

Methyl 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylate (150 mg, 40.4%) as a white solid:

¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.48-8.43 (m, 2H), 5.27-5.16 (m, 1H), 3.91 (s, 3H), 1.49 (d, J=6.4 Hz, 6H).

Methyl 2-isopropylpyrazolo[4,3-c]pyridine-6-carboxylate (70 mg, 19%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (d, J=1.2 Hz, 1H), 8.86 (s, 1H), 8.30 (s, 1H), 5.02-4.91 (m, 1H), 3.88 (s, 3H), 1.58 (d, J=6.8 Hz, 6H).

Step 2: 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylic acid

A mixture of methyl 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylate (50 mg, 0.23 mmol) and lithium hydroxide hydrate (27 mg, 1.14 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 25° C. for 18 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The mixture was concentrated under reduced pressure affording 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylic acid (40 mg, 85%) as a white solid, used in the next step without further purification.

Step 3: (S)-1-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

A mixture of 1-isopropylpyrazolo[4,3-c]pyridine-6-carboxylic acid (40 mg, 0.19 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (41 mg, 0.21 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.23 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (45 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 36-66%/0.05% ammonia in water) affording (S)-1-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide (32.7 mg, 43%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 9.02 (d, J=8.0 Hz, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.53-7.47 (m, 1H), 7.37-7.24 (m, 3H), 5.23-5.11 (m, 1H), 4.97-4.87 (m, 1H), 4.89-4.49 (m, 2H), 3.34 (s, 3H), 1.52-1.41 (m, 6H). LCMS R_(T)=0.834 min; m/z=380.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.834 min, ESI+ found [M+H]=380.0.

Example 214 is omitted.

Example 215 WX Method MMMMMM

1-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: ethyl 4-(4-methyl-5-nitro-1H-imidazol-1-yl)butanoate

A mixture of 5-methyl-4-nitro-1H-imidazole (58.0 g, 456.0 mmol), ethyl 4-bromobutyrate (107.0 g, 548.0 mmol) and potassium carbonate (75.7 g, 548.0 mmol) in N,N-dimethylformamide (250 mL) was stirred at 120° C. for 2 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×300 mL). The combined organics were washed with brine (2×50 mL), dried over sodium sulfate concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford ethyl 4-(4-methyl-5-nitro-1H-imidazol-1-yl)butanoate (33.6 g, 30%) as a yellow oil, used in the next step as is.

Step 2: ethyl 4-(5-amino-4-methyl-1H-imidazol-1-yl)butanoate

A mixture of ethyl 4-(4-methyl-5-nitro-1H-imidazol-1-yl)butanoate (33.6 g, 139.0 mmol) and 10% palladium on carbon (11.9 g, 11.2 mmol) in 1,4-dioxane (1.5 L) was hydrogenated (50 psi) at 25° C. for 24 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 4-(5-amino-4-methyl-1H-imidazol-1-yl)butanoate (33.4 g, 79%) as a black oil. LCMS R_(T)=1.366 min; m/z=212.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 1.366 min, ESI+ found [M+H]=212.2.

Step 3: 9-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

A mixture of ethyl 4-(5-amino-4-methyl-1H-imidazol-1-yl)butanoate (30.0 g, 142.0 mmol) and sodium ethoxide (48.3 g, 710.0 mmol) in ethanol (200 mL) was stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 9-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (8.0 g, 34%) as a yellow oil, used as is in the next step.

Step 4: 1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 9-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (2.0 g, 12.1 mmol) and cesium carbonate (3.9 g, 12.1 mmol) in N,N-dimethylformamide (30 mL) was added methyl iodide (1.72 g, 12.1 mmol). The reaction mixture was stirred at 25° C. for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (1.0 g, 46%) as a white solid, used as is in the next step.

Step 5: 3-iodo-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (100 mg, 0.56 mmol) in dichloromethane (10 mL) was added N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (872 mg, 6.7 mmol) and iodotrimethylsilane (1.3 g, 6.7 mmol) at −15° C. The mixture was stirred at −15° C. for 1.5 h and then iodine (849 mg, 3.35 mmol) was added in one portion. The reaction mixture was stirred at 30° C. for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 3-iodo-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (120 mg, 71%) as a light yellow solid. LCMS R_(T)=1.44 min; m/z=306.0 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.1% ammonium bicarbonate over 3 mins) retention time 1.44 min, ESI+ found [M+H]=306.0.

Step 6: 3-azido-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 3-iodo-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (120 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was added sodium azide (35 mg, 0.53 mmol). The reaction mixture was stirred at 25° C. for 2 h and diluted with ice water (5 mL). The solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 3-azido-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (80 mg, 92%) as a yellow solid. LCMS R_(T)=1.29 min; m/z=221.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3 mins) retention time 1.29 min, ESI+ found [M+H]=221.1

Step 7: 3-amino-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

A mixture of 3-azido-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (80 mg, 0.36 mmol) and 10% palladium on carbon (386 mg, 0.36 mmol) in methanol (20 mL) was hydrogenated (15 psi) at 25° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3-amino-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (60 mg, 85%) as a yellow oil, used in the next step without further purification.

Step 8: 1-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (20 mg, 0.1 mmol), 3-amino-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (19 mg, 0.1 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.12 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 30° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 10-40/0.05% ammonia hydroxide in water) to afford 1-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (7.2 mg, 19%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.55 (s, 1H), 7.41-7.33 (m, 5H), 5.47 (s, 2H), 4.87-4.54 (m, 1H), 4.36-4.31 (m, 1H), 3.98-3.91 (m, 1H), 3.35 (s, 3H), 2.75-2.63 (m, 1H), 2.22 (s, 3H), 2.15-2.07 (m, 1H).

LCMS R_(T)=0.91 min; m/z=380.3 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.91 min, ESI+ found [M+H]=380.3.

Example 216 WX Method TTTT

1-benzyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 6-amino-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-benzyltriazole-4-carboxylic acid (24 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile, 0.05% ammonia hydroxide in water) to give 1-benzyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide (8 mg, 16%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.92 (m, 2H), 7.76 (d, J=7.2, 2 H), 7.44-7.28 (m, 8H), 6.41 (s, 1H), 5.58 (s, 2H), 4.81-4.76 (m, 1H), 4.55-4.49 (m, 1H), 4.25-4.20 (m, 1H), 3.42 (s, 3H), 3.16-3.09 (m, 1H), 2.16-2.08 (m, 1H). LCMS R_(T)=0.72 min; m/z=442.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.72 min, ESI+ found [M+H]=442.0.

Example 217 WX Method CC

(S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide

Step 1: 2-chloro-7,7-dimethyl-5H-furo[3,4-d]pyrimidine

A mixture of 2,4-dichloro-7,7-dimethyl-5H-furo[3,4-d]pyrimidine (500 mg, 2.28 mmol) and zinc (448 mg, 6.85 mmol) in water (10 mL) was heated at reflux for 3 h. After cooled, the reaction mixture was extracted with dichloromethane (3×15 mL). The combined organic layers were washed water (3×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 2-chloro-7,7-dimethyl-5H-furo[3,4-d]pyrimidine (150 mg, 36%) as a white solid: LCMS R_(T)=1.54 min; m/z=185.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% ammonium bicarbonate over 1.5 mins) retention time 1.54/min, ESI+ found [M+H]=185.1.

Step 2: 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carbonitrile

A mixture of 2-chloro-7,7-dimethyl-5H-furo[3,4-d]pyrimidine (150 mg, 0.81 mmol), 1,4-diazabicyclo[2.2.2]octane (18 mg, 0.16 mmol) and sodium cyanide (40 mg, 0.81 mmol) in dimethyl sulfoxide (8 mL) and water (8 mL) was added stirred at 25° C. for 12 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (3×30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carbonitrile (80 mg, 56%) as a white solid: LCMS R_(T)=0.54 min; m z=175.9 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.54/min, ESI+ found [M+H]=175.9.

Step 3: methyl 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carboxylate

A solution of 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carbonitrile (80 mg, 0.46 mmol) in methanol (2 mL) was added acetyl chloride (72 mg, 0.91 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf=0.4) to afford methyl 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carboxylate (12 mg, 13%) as yellow oil: LCMS R_(T)=0.65 min; m/z=209.1 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 0.65/min, ESI+ found [M+H]=209.1.

Step 4: (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide

To a solution of methyl 7,7-dimethyl-5H-furo[3,4-d]pyrimidine-2-carboxylate (12 mg, 0.06 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (12 mg, 0.06 mmol) in tetrahydrofuran (4 mL) was added trimethylaluminum (2.0 M, 0.17 mL, 0.35 mmol). The mixture was stirred at 25° C. for 12 h and then quenched by addition of saturated aqueous ammonium chloride. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 27-57/0.05% ammonia hydroxide in water) to afford (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide (4 mg, 19%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.47-7.45 (m, 1H), 7.35-7.32 (m, 2H), 7.28-7.27 (m, 1H), 5.16 (s, 2H), 5.06-5.04 (m, 1H), 4.69-4.68 (m, 1H), 4.52-4.47 (m, 1H), 3.45 (s, 3H), 1.54 (s, 6H).

LCMS R_(T)=1.53 min; m/z=369.1 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.53/min, ESI+ found [M+H]=369.1.

Example 218 WX Method P

(S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxamide

Step 1: 2-chloro-7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine

A mixture of 2,4-dichloro-7,7-dimethyl-5H-thieno[3,4-d]pyrimidine (1.0 g, 4.3 mmol) and zinc (0.8 g, 12.8 mmol) in water (20 mL) was heated at 100° C. for 12 h. After cooled, the mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to afford 2-chloro-7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine (400 mg, 47%) as a white solid: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.60 (s, 1H), 4.18 (s, 2H), 1.69 (s, 6H).

Step 2: 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carbonitrile

To a solution of 2-chloro-7,7-dimethyl-5H-thieno[3,4-d]pyrimidine (250 mg, 1.25 mmol) in dimethyl sulfoxide (10 mL) and water (10 mL) was added sodiumcyanide (122 mg, 2.49 mmol) and 1,4-diazabicyclo[2.2.2]octane (28 mg, 0.25 mmol). The reaction mixture was stirred at 30° C. for 12 h and then diluted with ethyl acetate (20 mL). The organic layer was washed with water (3×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carbonitrile (150 mg, 63%) as a white solid, used as is in the next step.

Step 3: methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate

To a solution of 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carbonitrile (40 mg, 0.18 mmol) in methanol (3 mL) was added acetyl chloride (140 mg, 1.78 mmol). The reaction mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure to afford crude methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate (38 mg, 95%) as a white solid: LCMS R_(T)=1.5 min; m/z=224.9 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.1% trifluoroacetic over 1.5 mins) retention time 0.600 min, ESI+ found [M+H]+=224.9

Step 4: (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxamide

To a solution of methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate (38 mg, 0.17 mmol) in tetrahydrofuran (4 mL) and was added (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (36 mg, 0.19 mmol) and trimethylaluminum (2.0 M, 0.5 mL, 1.00 mmol). The reaction mixture was stirred at 30° C. for 12 h and then concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17-47/0.05% FA in water) to afford (S)-7,7-dimethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxamide (2.1 mg, 3%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 7.45-7.41 (m, 1H), 7.34-7.28 (m, 2H), 7.25-7.22 (m, 1H), 4.69-4.63 (m, 2H), 4.44-4.39 (m, 1H), 4.23 (s, 2H), 3.42 (s, 3H), 1.71 (s, 6H). LCMS R_(T)=1.065 min; m/z=385.2 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.1% trifluoroacetic over 2 mins) retention time 1.065 min, ESI+ found [M+H]+=385.2

Example 219 WX Method QQ

(S)-1-(2,3-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(2,3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (37 mg, 0.15 mmol), (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (30 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to afford 1-[(2,3-difluorophenyl)methyl]-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (15.5 mg, 36%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.52 (d, J=8.0 Hz, 1H), 7.48-7.41 (m, 1H), 7.27-7.15 (m, 2H), 6.12 (s, 1H), 5.61 (s, 2H), 4.34-4.23 (m, 2H), 4.11-4.04 (m, 1H), 3.21 (s, 3H), 2.62-2.54 (m, 1H), 2.36-2.28 (m, 1H), 2.16 (s, 3H).

LCMS R_(T)=1.143 min; m/z=416.3 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.143 min, ESI+ found [M+H]⁺=416.3

Example 220 WX Method RR

(S)-1-(3,4-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (37 mg, 0.15 mmol), (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (30 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 23-53%/0.05% ammonium hydroxide in water) to afford (S)-1-(3,4-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (18.1 mg, 41%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.52 (d, J=8.0 Hz, 1H), 7.49-7.41 (m, 2H), 7.19-7.17 (m, 1H), 6.12 (s, 1H), 5.48 (s, 2H), 4.35-4.23 (m, 2H), 4.11-4.04 (m, 1H), 3.21 (s, 3H), 2.62-2.54 (m, 1H), 2.36-2.28 (m, 1H), 2.16 (s, 3H). LCMS R_(T)=1.158 min; m/z=416.3 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.158 min, ESI+ found [M+H]⁺=416.3.

Example 221 WX Method WW

(S)-1-(2,4-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (30 mg, 0.12 mmol), (6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H- pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (28 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-50%/0.05% ammonia hydroxide in water) to afford (S)-1-(2,4-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (32 mg, 74%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.48-7.45 (m, 1H), 7.05-7.00 (m, 2H), 6.11 (s, 1H), 5.52 (s, 2H), 4.54-4.49 (m, 1H), 4.33-4.23 (m, 2H), 3.32 (s, 3H), 2.85-2.83 (m, 1H), 2.25-2.24 (m, 4H). LCMS R_(T)=0.760 min; m/z=416.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.760 min, ESI+ found [M+H]=416.1

Example 222 WX Method XX

(S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (27 mg, 0.12 mmol), (6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (28 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-50%/0.05% ammonia hydroxide in water) to afford (S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (31.4 mg, 80%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.42-7.38 (m, 2H), 7.12-7.08 (m, 2H), 6.11 (s, 1H), 5.46 (s, 2H), 4.55-4.50 (m, 1H), 4.30-4.22 (m, 2H), 3.32 (s, 3H), 2.86-2.80 (m, 1H), 2.29-2.23 (m, 4H). LCMS R_(T)=3.87 min; m/z=424.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.745 min, ESI+ found [M+H]=398.0.

Example 223 WX Method AAAA

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: Methyl 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylate

To a mixture of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.7 mmol) and potassium carbonate (21.8 g, 157.4 mmol) in N,N-dimethylformamide (200 mL) was added 3,4-difluorobenzyl chloride (19.6 g, 94.4 mmol) dropwise at 0° C. The mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (6.7 g, 34%) as white solid, used in the next step as is.

Step 2: 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (2.0 g, 7.9 mmol) and potassium hydroxide (886 mg, 15.8 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (20 mL). The aqueous solution was adjusted to pH=4 by addition of hydrochloric acid (1.0 M). The solid product was collected by filtration, washed with water (3×25 mL) and dried under vacuum to afford 1-[(3, 4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (1.6 g, 85%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.66 (s, 1H), 7.36-7.21 (m, 3H), 5.47 (s, 2H).

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (26 mg, 0.11 mmol), (6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol). and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% HCl in water) to give (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (26 mg, 65%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.78 (s, 1H), 7.36-7.20 (m, 3H), 6.29 (s, 1H), 5.49 (s, 2H), 4.71-4.67 (m, 1H), 4.45-4.35 (m, 2H), 3.21 (s, 3H), 2.88-2.86 (m, 1H), 2.40-2.38 (m, 1H), 1.12-1.11 (m, 2H), 0.90-0.88 (m, 2H). LCMS R_(T)=1.02 min; m/z=442.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.02 min, ESI+ found [M+H]=442.2.

Example 224 WX Method EEEE

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (26 mg, 0.11 mmol), (6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (24 mg, 0.14 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (27-57% acetonitrile in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (27.9 mg, 70%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.50-7.46 (m, 1H), 7.06-6.99 (m, 2H), 6.00 (s, 1H), 5.53 (s, 2H), 4.52-4.49 (m, 1H), 4.29-4.19 (m, 2H), 3.18 (s, 3H), 2.85-2.80 (m, 1H), 2.25-2.23 (m, 1H), 1.92-1.89 (m, 1H), 0.95-0.92 (m, 2H), 0.75-0.72 (m, 2H). LCMS R_(T)=0.79 min; m/z=442.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=442.1.

Example 225 WX Method GGGG

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (24 mg, 0.11 mmol), (6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (27-57% acetonitrile in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (29.9 mg, 78%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.40-7.36 (m, 2H), 7.10-7.06 (m, 2H), 5.98 (s, 1H), 5.44 (s, 2H), 4.51-4.47 (m, 1H), 4.27-4.18 (m, 2H), 3.29 (s, 3H), 2.84-2.78 (m, 1H), 2.24-2.21 (m, 1H), 1.90-1.85 (m, 1H), 0.92-0.90 (m, 2H), 0.72-0.70 (m, 2H). LCMS R_(T)=0.78 min; m/z=424.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=424.1

Example 226 WX Method NNNNNN

5-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (21 mg, 0.10 mmol), 3-amino-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (20 mg, 0.10 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.12 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 10-40/0.05% ammonia hydroxide in water) to afford 5-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (2.4 mg, 6%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.55 (s, 1H), 7.34-7.24 (m, 5H), 4.57-4.55 (m, 1H), 4.37-4.31 (m, 1H), 4.18-4.16 (m, 2H), 3.97-3.91 (m, 1H), 3.31 (s, 3H), 2.72-2.65 (m, 1H), 2.22 (s, 3H), 2.11-2.07 (m, 1H).

LCMS R_(T)=0.84 min; m/z=380.2 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.84/min, ESI+ found [M+H]=380.2.

Example 227 WX Method OOOOOO

1-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (21 mg, 0.10 mmol), 3-amino-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (20 mg, 0.10 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.12 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 15-45/0.05% ammonia hydroxide in water) to afford 1-benzyl-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,3-triazole-4-carboxamide (7 mg, 18%), as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.55 (s, 1H), 7.40-7.33 (m, 5H), 5.64 (s, 2H), 4.58-4.53 (m, 1H), 4.37-4.32 (m, 1H), 3.97-3.92 (m, 1H), 3.31 (s, 3H), 2.70-2.64 (m, 1H), 2.22 (s, 3H), 2.17-2.12 (m, 1H).

LCMS R_(T)=0.94 min; m/z=380.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% trifluoacetic acid over 2 mins) retention time 0.94/min, ESI+ found [M+H]=380.1.

Example 228 WX Method KK

(S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide

Step 1: Methyl 5-isopropenyl-1h-indazole-3-carboxylate

A mixture of methyl 5-bromo-1h-indazole-3-carboxylate (400 mg, 1.56 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (114 mg, 0.16 mmol), cesium carbonate (1000 mg, 3.14 mmol) and potassium isopropenyltrifluoroborate (348 mg, 2.36 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl 5-isopropenyl-1 h-indazole-3-carboxylate (175 mg, 52%) as a white solid: LCMS R_(T)=3.173 min; m/z=216.9 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid 7 mins) retention time 3.173 min, ESI+ found [M+H]=216.9.

Step 2: Methyl 5-isopropyl-1h-indazole-3-carboxylate

A mixture of methyl 5-isopropenyl-1h-indazole-3-carboxylate (70 mg, 0.32 mmol) and 10% palladium on carbon (35 mg, 0.32 mmol) in methanol (5 mL) was hydrogenated (15 psi) at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure affording crude methyl 5-isopropyl-1h-indazole-3-carboxylate (64 mg, 91%) as a pale yellow solid: LCMS R_(T)=3.307 min; m/z=219.0 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid 7 mins) retention time 3.307 min, ESI+ found [M+H]⁺=219.0.

Step 3: 5-isopropyl-1h-indazole-3-carboxylic acid

A mixture of methyl 5-isopropyl-1H-indazole-3-carboxylate (64 mg, 0.29 mmol) and lithium hydroxide hydrate (35 mg, 1.47 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 25° C. for 18 h. The organic solvent was removed under reduced pressure, and the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The solid was removed by filtration and the aqueous layer was concentrated under reduced pressure affording 5-isopropyl-1H-indazole-3-carboxylic acid (40 mg, 67%) as a white solid: LCMS R_(T)=1.711 min; m/z=205.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.04% formic acid over 3 mins) retention time 1.711 min, ESI+ found [M+H]=205.1

Step 4: (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide

A mixture of (3s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (41 mg, 0.22 mmol), 5-isopropyl-h-indazole-3-carboxylic acid (40 mg, 0.20 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (45 mg, 0.24 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonia in water) affording (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-indazole-3-carboxamide (31.5 mg, 41.5% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 13.65 (br.s, 1H), 8.38 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.60-7.49 (m, 2H), 7.40-7.23 (m, 4H), 4.99-4.89 (m, 1H), 4.68-4.58 (m, 1H), 4.52-4.43 (m, 1H), 3.34 (s, 3H), 3.04-2.93 (m, 1H), 1.22 (d, J=6.8 Hz, 6H). LCMS R_(T)=1.173 min; m/z=379.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid 7 mins) retention time 1.173 min, ESI+ found [M+H]=379.1.

Example 229 WX Method Z

1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

Step 1: 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)furo[3,4-c]pyridin-3(1H)-one

To a solution of 2,2,6,6-tetramethylpiperidine (13.5 g, 95.6 mmol) in tetrahydrofuran (300 mL) was added n-butyllithium (2.5 M, 50.0 mL, 125.0 mmol) at −78° C. The reaction was stirred at −78° C. for 1 h, and 6-chloronicotinic acid (5.0 g, 31.7 mmol) in tetrahydrofuran (30 mL) was added. Stirring at −78° C. was continued for 2 h, then 4,4,4-trifluorobutan-2-one (4.0 g, 31.7 mmol) was added. After addition, the reaction mixture was warmed up to 25° C. for 16 h and then quenched by addition of saturated aqueous ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)furo[3,4-c]pyridin-3(1H)-one (4.0 g, 47%) as yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 7.48 (s, 1H), 2.95-2.88 (m, 1H), 2.82-2.76 (m, 1H), 1.77 (s, 3H).

Step 2: 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridin-3-ol

To a solution of 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)furo[3,4-c]pyridine-3(1H)-one (3.5 g, 13.2 mmol) in toluene (15 mL) was added diisobutylaluminum hydride (1.0 M, 26.4 mL, 26.4 mmol) dropwise at −70° C. After addition, stirring at −70° C. was continued for 2 h and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridin-3-ol (3.5 g, 99%) as yellow oil, used as is in the next step.

Step 3: 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine

To a solution of 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridin-3-ol (3.4 g, 12.7 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (7.2 g, 63.5 mmol) dropwise at 0° C. The reaction was stirred for 30 min at 0° C., and triethyl silane (7.4 g, 63.5 mmol) was added. After addition, the mixture was allowed to warm to 25° C. over 3 h and then quenched by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to afford 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine (3.0 g, 94%) as yellow oil, used as is in the next step.

Step 4: methyl 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate

A solution of 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine (3.0 g, 11.9 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (872 mg, 1.19 mmol) and triethylamine (6.0 g, 59.6 mmol) in methanol (80 mL) was heated to 80° C. for 4 h under carbon oxide (40 psi). The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (2.5 g, 76%) as yellow oil, used as is in the next step.

Step 5: 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid

A mixture of methyl 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (2.5 g, 9.1 mmol) and lithium hydroxide hydrate (1.9 g, 45.4 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was stirred at 25° C. for 2 h. The organic solvent was evaporated under reduced pressure and the resulting aqueous layer was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (2.3 g, 91%) as a yellow solid, used in the next step without further purification.

Step 6: 1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (49 mg, 0.19 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (25 mg, 0.19 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (30 mg, 0.16 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (36 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 43-73% with 0.05% HCl in water) to afford 1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (45.7 mg, 67%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 8.05 (s, 1H), 7.46-7.43 (m, 1H), 7.34-7.31 (m, 2H), 7.27-7.24 (m, 1H), 5.21 (s, 2H), 5.04-5.01 (m, 1H), 4.67-4.62 (m, 1H), 4.44-4.41 (m, 1H), 3.43 (s, 3H), 2.90-2.79 (m, 2H), 1.57 (s, 3H). LCMS R_(T)=0.878 min; m/z=436.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.878 min, ESI+ found [M+H]=436.1.

Example 230 WX Method U

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl) imidazo[1,5-c]pyrimidine-1-carboxamide

Step 1: ethyl 2-((diphenylmethylene)amino)-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate

To a solution of 2-((diphenylmethylene)amino)acetate (3.0 g, 11.2 mmol) in tetrahydrofuran (60 mL) was added potassium tert-butoxide (1.0 M, 12.3 mL, 12.3 mmol) dropwise at −78° C. After stirred for 30 min at −78° C., 4-chloro-6-trifluoromethylpyrimidine (3.1 g, 16.8 mmol) was added and the resulting mixture was allowed to warm to 0° C. and stirred for another 0.5 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford ethyl 2-((diphenylmethylene)amino)-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate (3.5 g, 23%) as red oil: LCMS R_(T)=1.001 min; m/z=414.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 1.001 min, ESI+ found [M+H]=414.0.

Step 2: ethyl 2-amino-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate hydrochloride

A mixture of ethyl 2-((diphenylmethylene)amino)-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate (3.5 g, 2.5 mmol) and hydrochloric acid (36%, 514 mg, 5.08 mmol) in dichloromethane (25 mL) was stirred at 25° C. for 1 h. The solution was diluted with water (20 mL) and washed with dichloromethane (2×25 mL). The aqueous phase was concentrated to dryness to afford crude ethyl 2-amino-2-(6-(trifluoromethyl) pyrimidin-4-yl)acetate hydrochloride (600 mg, 95%) as yellow oil: LCMS R_(T)=0.244 min; m/z=249.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.244 min, ESI+ found [M+H]=249.8.

Step 3: ethyl 7-(trifluoromethyl)imidazo[1,5-c]pyrimidine-1-carboxylate

Formic acid (98%, 2 mL) was added dropwise to acetic anhydride (4.0 mL) at 0° C. The resulting solution was stirred for 4 h at 0° C., and then added to a solution of ethyl 2-amino-2-(6-(trifluoromethyl)pyrimidin-4-yl)acetate hydrochloride (600 mg, 2.41 mmol) in tetrahydrofuran (10 mL) at 0° C. After addition, the mixture was stirred at 25° C. for 6 h, and then diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl 7-(trifluoromethyl)imidazo[1,5-c]pyrimidine-1-carboxylate (600 mg, 96%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 4.50-4.45 (m, 2H), 1.45 (t, J=7.2 Hz, 3H).

Step 4: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl) imidazo[1,5-c]pyrimidine-1-carboxamide

To a mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol) and ethyl 7-(trifluoromethyl)imidazo[1,5-c]pyrimidine-1-carboxylate (60.67 mg, 0.23 mmol) in tetrahydrofuran (3 mL) was added trimethylaluminum (2.0 M, 0.78 mL, 1.56 mmol). The mixture was stirred at 50° C. for 15 h and then quenched by addition of saturated aqueous potassium sodium tartrate (10 mL). The solution was stirred at 25° C. for 1 h and then extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (32-62% acetonitrile in water and 0.05% ammonium hydroxide) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoromethyl)imidazo[1,5-c]pyrimidine-1-carboxamide (31 mg, 27%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (s, 1H), 8.82 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.34-7.25 (m, 3H), 4.95-4.89 (m, 1H), 4.66-4.61 (m, 1H), 4.47-4.29 (m, 1H), 3.33 (s, 3H): LCMS R_(T)=0.845 min; m/z=406.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.845 min, ESI+ found [M+H]=406.0.

Example 231 WX Method DD

1-(methoxymethyl)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

Step 1: 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridin-3-one

To a stirred solution of 2,2,6,6-tetramethylpiperidine (4.1 g, 29.0 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M, 15 mL, 37.5 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 40 min and then 6-chloronicotinic acid (1.5 g, 9.5 mmol) in tetrahydrofuran (20 mL) was added. The resulting mixture was stirred at −78° C. for another 2 h, and then methoxyacetone (839 mg, 9.52 mmol) was added dropwise. After addition, the reaction was warmed up to 25° C. and stirred for 16 h before quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate/petroleum ether) to afford 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridin-3-one (1.5 g, 69%) as yellow oil, use in the next step as is

Step 2: 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridin-3-ol

To a solution of 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridin-3-one (1.5 g, 6.6 mmol) in toluene (40 mL) was added diisobutylaluminum hydride (1.0 M, 13.0 mL, 13.0 mmol) dropwise at −70° C. After addition, stirring at −70° C. was continued for 2 h and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridin-3-ol (1.5 g, 99%) as yellow oil, used in the next step without further purification.

Step 3: 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine

To a solution of 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridin-3-ol (280 mg, 1.22 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (695 mg, 6.10 mmol) dropwise at 0° C. The reaction was stirred for 30 min at 0° C., and triethyl silane (425 mg, 3.66 mmol) was added. After addition, the mixture was allowed to warm to 25° C. over 3 h and then quenched by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine (200 mg, 77%) as yellow oil: LCMS R_(T)=0.45 min; m/z=214.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.45/min, ESI+ found [M+H]=214.1.

Step 4: methyl 1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate

A solution of 6-chloro-1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine (200 mg, 0.94 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (68 mg, 0.09 mmol) and triethylamine (947 mg, 9.36 mmol) in methanol (10 mL) was heated at 80° C. for 12 h under carbon oxide (25 psi). The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford methyl 1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate (160 mg, 72%) as yellow oil: LCMS R_(T)=0.52 min; m/z=238.0 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.52/min, ESI+ found [M+H]=238.0

Step 5: 1-(methoxymethyl)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

To a solution of methyl 1-(methoxymethyl)-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate (20 mg, 0.08 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (18 mg, 0.09 mmol) in tetrahydrofuran (4 mL) was added and trimethylaluminum (2.0 M, 0.25 mL, 0.51 mmol). The reaction mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 30-60/0.05% ammonia hydroxide in water) to afford 1-(methoxymethyl)-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (2 mg, 7%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.93 (s, 1H), 7.45-7.43 (m, 1H), 7.34-7.32 (m, 2H), 7.26-7.24 (m, 1H), 5.18 (s, 2H), 5.05-5.00 (m, 1H), 4.67-4.65 (m, 2H), 4.43-4.40 (m, 1H), 3.57-3.51 (m, 2H), 3.43 (s, 3H), 3.27 (s, 3H), 1.46 (s, 3H). LCMS R_(T)=1.73 min; m/z=398.1 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.73/min, ESI+ found [M+H]=398.1

Example 232 WX Method Q

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5-dihydro-2H,3′ H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxamide

Step 1: 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridin]-3′-one

To a stirred solution of lithium diisopropylamide (2.0 M, 12.7 mL, 25.4 mmol) in tetrahydrofuran (50 mL) was added a solution of 6-chloronicotinic acid (1.0 g, 6.35 mmol) in tetrahydrofuran (10 mL) at −78° C. After addition, the mixture was stirred at −78° C. for 3 h, and then a solution of 3-oxotetrahydrofuran (5.5 g, 63.5 mmol) in tetrahydrofuran (10 mL) was added. The resulting mixture was warmed up to 25° C. and stirred for 12 h before quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-40% methanol in dichloromethane) affording 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridin]-3′-one (0.6 g, 41.8%) as a yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 7.90 (s, 1H), 4.29-4.13 (m, 2H), 4.09 (s, 2H), 2.70-2.38 (m, 2H). LCMS R_(T)=0.995 min; m/z=226 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 0.995 min, ESI+ found [M+H]=226

Step 2: 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridin]-3′-ol

To a solution of 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridin]-3′-one (550 mg, 2.44 mmol) in toluene (65 mL) was added diisobutylaluminumhydride (1.0 M, 7.3 mL, 7.3 mmol) dropwise at −70° C. After addition, the mixture was stirred at −60° C. for 4 h and then quenched by addition of saturated aqueous ammonium chloride (70 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with aqueous NaOH (2%, 2×50 mL) and water (20 mL). The combined aqueous layers were adjusted to pH=4 by addition of hydrochloric acid (2.0 M) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure affording crude 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridin]-3′-ol (450 mg, 81%) as yellow oil: LCMS R_(T)=0.521 min; m/z=228.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 0.521 min, ESI+ found [M+H]=228.1

Step 3: 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine

A mixture of 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridin]-3′-ol (450 mg, 2.0 mmol) and trifluoroacetic acid (1.1 g, 9.9 mmol) in dichloromethane (20 mL) was stirred for 0.5 h at 0° C., and then triethylsilane (689 mg, 5.9 mmol) was added. The resulting mixture was warmed up to 25° C. and stirred for 50 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethylacetae in petroleum) to afford 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine (140 mg, 33%) as colorless oil: LCMS R_(T)=1.119 min; m/z=212.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 min) retention time 1.119 min, ESI+ found [M+H]=212.1.

Step 4: methyl 4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxylate

A mixture of 6′-chloro-4,5-dihydro-2H,3′H-spiro[furan-3, 1′-furo[3,4-c]pyridine (140 mg, 0.66 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (48 mg, 0.07 mmol) and triethylamine (669 mg, 6.6 mmol) in methanol (15 mL) was stirred at 80° C. for 12 h under carbon oxide (50 psi). The mixture was concentrated and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 70% ethyl acetate in petroleum ether) to afford methyl 4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxylate (40 mg, 25%) as brown oil, used in the next step as is.

Step 5: 4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxylic acid

A mixture of 4,5-dihydro-2H,3′H-spiro[furan-3, 1′-furo[3,4-c]pyridine]-6′-carboxylate (40 mg, 0.17 mmol) and potassium hydroxide (28 mg, 0.51 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred for 1 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The aqueous layer was concentrated under reduced pressure to afford crude 4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxylic acid (11 mg, 30%) as a yellow solid, used in the next step as is.

Step 6: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5-dihydro-2H,3′ H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxamide

A mixture of 4,5-dihydro-2H, 3′H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxylic acid (11 mg, 0.05 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (11 mg, 0.08 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (15.0 mg, 0.08 mmol) and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (10 mg, 0.05 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The solvent was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.225% FA in water) to afford N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5-dihydro-2H,3′H-spiro[furan-3,1′-furo[3,4-c]pyridine]-6′-carboxamide (14 mg, 70.8%) as yellow oil: ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.99 (s, 1H), 7.47-7.41 (m, 1H), 7.37-7.28 (m, 2H), 7.27-7.21 (m, 1H), 5.18 (s, 2H), 5.00-5.05 (m, 1H), 4.67-4.61 (m, 1H), 4.44-4.36 (m, 1H), 4.15-4.02 (m, 2H), 3.96-3.99 (m, 1H), 3.90-3.83 (m, 1H), 3.43 (s, 3H), 2.38-2.23 (m, 2H). LCMS R_(T)=0796 min; m/z=396 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 min) retention time 0.796 min, ESI+ found [M+H]+=396.

Example 233 WX Method QQQQQQ

(1R)-1-ethyl-1-methyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo [1,2-a][1,3]diazepin-7-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

Step 1: ethyl 4-(2-nitroimidazol-1-yl)butanoate

A mixture of 2-nitroimidazole (10.0 g, 88.4 mmol), ethyl 4-bromobutyrate (17.2 g, 88.4 mmol) and potassium carbonate (22.4 g, 176.9 mol) in N,N-dimethylformamide (20 mL) was heated to 120° C. for 2 h. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give ethyl 4-(2-nitroimidazol-1-yl)butanoate (9.0 g, 45%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=10.4 Hz, 2H), 4.48 (t, J=7.2 Hz, 2H), 4.16-4.08 (m, 3H), 2.35 (t, J=7.2 Hz, 2H), 2.20-2.15 (m, 2H), 1.28-1.20 (m, 4H).

Step 2: ethyl 4-(2-amino-1H-imidazol-1-yl)butanoate

A mixture of ethyl 4-(2-nitroimidazol-1-yl)butanoate (7.0 g, 30.8 mmol) and 10% palladium on carbon (32.8 g, 30.8 mmol) in 1,4-dioxane (300 mL) was hydrogenated (15 psi) at 25° C. for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 4-(2-amino-1H-imidazol-1-yl)butanoate (5.0 g, 81%) as a brown oil, used in the next step without further purification.

Step 3: 6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

To a solution of ethyl 4-(2-amino-1H-imidazol-1-yl)butanoate (4.5 g, 22.8 mmol) in ethanol (50 mL) was added sodium ethoxide (7.7 g, 114.1 mmol). The mixture was stirred at 25° C. for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give 6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (2.0 g, 58%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (br. s, 1H), 7.00 (s, 1H), 6.71 (s, 1H), 4.01 (t, J=6.8 Hz, 2H), 2.29-2.21 (m, 2H), 2.19-2.06 (m, 2H).

Step 4: 9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

To a solution of 6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (1.8 g, 11.9 mmol) in N,N-dimethylformamide (50 mL) was added cesium carbonate (3.9 g, 11.9 mmol) and iodomethane (1.7 g, 11.9 mmol). The mixture was stirred at 25° C. for 3 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (1.5 g, 76%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.04 (d, J=1.6 Hz, 1H), 6.79 (d, J=1.2 Hz, 1H), 3.99 (t, J=6.8 Hz, 2H), 3.17 (s, 3H), 2.23-2.13 (m, 4H).

Step 5: 7-azido-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

To a mixture of 9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (1.2 g, 7.3 mmol) in tetrahydrofuran (50 mL) was added lithium diisopropylamide (2.0 M, 10.9 mL, 21.7 mmol) dropwise at −78° C. After stirred at −78° C. for 30 min, p-toluenesulfonylazide (4.3 g, 21.8 mmol) in tetrahydrofuran (5 mL) was added. After addition, the mixture was stirred at −78° C. for 2 h then allowed to warm to 25° C. for another 15 h. The reaction was quenched by addition of acetic acid (0.4 mL) and stirred for 3 h at 25° C. Then the mixture was adjust to pH=8 by addition of saturated aqueous sodium carbonate. The mixture was concentrated to dryness and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 7-azido-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (800 mg, 53%) as yellow oil, used as is in the next step.

Step 6: 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

A mixture of 7-azido-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (800 mg, 3.8 mmol) and 10% palladium on carbon (50 mg, 0.05 mmol) in methanol (10 mL) was hydrogenated (15 psi) at 25° C. for 15 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (300 mg, 43%) as yellow oil, used in the next step without further purification.

Step 7: (1R)-1-ethyl-1-methyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (23 mg, 0.11 mmol), 7-amino-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (20 mg, 0.11 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (26 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-50/0.05% ammonia hydroxide in water) to afford (1R)-1-ethyl-1-methyl-N-(9-methyl-8-oxo-6, 7,8, 9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (4 mg, 9.9%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.87 (s, 1H), 7.13 (s, 1H), 7.00-6.99 (m, 1H), 5.21-5.13 (m, 2H), 4.58-4.55 (m, 1H), 4.35-4.30 (m, 1H), 4.12-4.10 (m, 1H), 3.41 (s, 3H), 2.95-2.92 (m, 1H), 2.32-2.26 (m, 1H), 1.89-1.83 (m, 2H), 1.47 (s, 3H), 0.80-0.76 (m, 3H). LCMS R_(T)=1.81 min; m/z=370.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.81 min, ESI+ found [M+H]=370.1.

Example 234 WX Method WWWW

1-benzyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: N-(3-bromo-1H-pyrazol-5-yl)formamide

A mixture of 3-bromo-1H-pyrazol-5-amine (16.0 g, 98.8 mmol) and formic acid (50 mL, 98.8 mmol) was stirred at 110° C. in a sealed vessel for 2 h. The mixture was concentrated under reduced pressure and the residue was washed with water (50 mL) to give N-(3-bromo-1H-pyrazol-5-yl)formamide (15.0 g, 80%) as a white solid, used in the next step without further purification.

Step 2: 3-bromo-N-methyl-1H-pyrazol-5-amine

To a solution of N-(3-bromo-1H-pyrazol-5-yl)formamide (15.0 g, 79.0 mmol) in tetrahydrofuran (200 mL) was added borane (1.0 M, 315.8 mL, 315.8 mmol). The mixture was stirred at 0° C. for 2 h and then quenched by addition of methanol (30 mL) and hydrochloric acid (10%, 5 mL). The mixture was then heated at reflux for 30 min and adjusted to pH=8 by addition of aqueous sodium hydroxide (10%). The mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate (100 mL), washed with water (2×50 mL), brine (50 mL), dried over magnesium sulfate and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 3-bromo-N-methyl-1H-pyrazol-5-amine (13.0 g, 94%) as a white solid, used as is in the next step.

Step 3: N-(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide

A mixture of 3-bromo-N-methyl-1H-pyrazol-5-amine (13.5 g, 76.7 mmol) and 4-chlorobutanoyl chloride (33.5 mL, 300 mmol) was stirred at 60° C. for 3 h. After cooled, methanol (50 mL) was added into the mixture carefully and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give N-(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide (17.0 g, 79%) as a colorless oil, used in the next step without further purification.

Step 4: 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a mixture of N-(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide (17.0 g, 60.6 mmol) in N,N-dimethylformamide (100 mL) was added cesium carbonate (39.5 g, 121.2 mmol) and stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with ethyl acetate (200 mL). The mixture was washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (12.0 g, 76%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 6.05 (s, 1H), 4.22 (t, J=6.4 Hz, 2H), 3.24 (s, 3H), 2.43-2.32 (m, 4H).

Step 5: 2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (500 mg, 2.1 mmol), 3,6-dihydro-2h-pyran-4-boronicacidpinacolester (646 mg, 3.1 mmol), 1,1′-bis(diphenylphosphino) ferrocene palladium dichloride (150 mg, 0.2 mmol) and potassium carbonate (566 mg, 4.1 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was heated 15 to 110° C. for 30 min under microwave conditions. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf=0.3) to afford 2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (400 mg, 79%) as white solid. LCMS R_(T)=1.14 min; m/z=248.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.14 min, ESI+ found M+H]=248.1

Step 6: 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (650 mg, 2.6 mmol) and 10% palladium on carbon (2.8 g, 2.6 mmol) in methanol (20 mL) was hydrogenated (15 psi) at 25° C. for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (510 mg, 78%) as white solid: LCMS R_(T)=0.574 min; m/z=250.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.574 min, ESI+ found [M+H]=250.1

Step 7: 6-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (510 mg, 2.1 mmol) in dichloromethane (20 mL) was added N1,N1,N2,N2-tetramethylethane-1,2-diamine (1.4 g, 12.3 mmol), followed by iodotrimethylsilane (2.5 g, 12.3 mmol) at −15° C. The resulting solution was stirred 2 h at −15 OC, and iodine (1.6 g, 6.1 mmol) was added in one portion. After stirred for 2 h at −15° C., the reaction mixture was quenched by addition of saturated sodium bisulfite (30 mL). The mixture was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 6-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (520 mg, 67.7% yield) as brown solid: LCMS R_(T)=0.65 min; m/z=376.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.65 min, ESI+ found [M+H]=376.0

Step 8: 6-azido-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 6-iodo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (510 mg, 1.4 mmol) and sodium azide (106 mg, 1.6 mmol) in N,N-dimethylformamide (2 mL) was stirred for 2 h at 25° C. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 6-azido-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (340 mg, 86%) as a light yellow oil: LCMS R_(T)=0.63 min; m/z=291.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.63 min, ESI+ found [M+H]=291.2

Step 9: 6-amino-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 6-azido-4-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (340 mg, 1.2 mmol) and 10% palladium on carbon (124 mg, 0.12 mmol) in methanol (30 mL) was hydrogenated (15 psi) at 25° C. for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude 6-amino-4-methyl-2-tetrahydropyran-4-yl-7,8 dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (300 mg, 97%) as white solid, used in the next step without further purification.

Step 10: 1-benzyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-4-methyl-2-tetrahydropyran-4-yl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.08 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (15.4 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (18 mg, 0.11 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (25-35% acetonitrile in water and 0.05% ammonia hydroxide) to afford 1-benzyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (26.3 mg, 76%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.36-7.32 (m, 5H), 6.19 (s, 1H), 5.47 (s, 2H), 4.53-4.51 (m, 1H), 4.50-4.48 (m, 1H), 4.33-4.31 (m, 1H), 4.01-3.99 (m, 2H), 3.57-3.51 (m, 2H), 3.33 (s, 3H), 2.89-2.84 (m, 2H), 2.26-2.25 (m, 1H), 1.90-1.85 (m, 2H), 1.79-1.75 (m, 2H). LCMS R_(T)=1.67 min; m/z=450.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.67 min, ESI+ found [M+H]=450.2.

Example 235 WX Method XXXX

5-benzyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-4-methyl-2-tetrahydropyran-4-yl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.08 mmol), 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (15 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethyl propane-1,3-diamine hydrochloride (18 mg, 0.11 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (10-40% acetonitrile in water and 0.05% ammonia hydroxide) to afford 5-benzyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (11.4 mg, 32%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.20 (m, 5H), 6.19 (s, 1H), 4.30-4.28 (m, 2H), 4.25-4.22 (m, 3H), 3.87-3.84 (m, 2H), 3.30-3.26 (m, 2H), 3.18 (s, 3H), 2.78-2.73 (m, 1H), 2.42-2.40 (m, 2H), 1.80-1.56 (m, 4H). LCMS R_(T)=1.64 min; m/z=450.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.64 min, ESI+ found [M+H]=450.2.

Example 236 WX Method ZZZZ

(1R)-1-ethyl-1-methyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of 6-amino-4-methyl-2-tetrahydropyran-4-yl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.08 mmol), (R)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (15 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (18 mg, 0.11 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (31-61% acetonitrile in water and 0.05% ammonia hydroxide) to afford (1R)-1-ethyl-1-methyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (16 mg, 46%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.86 (s, 1H), 6.20 (s, 1H), 5.16-5.15 (m, 2H), 4.59-4.52 (m, 1H), 4.36-4.34 (m, 1H), 4.29-4.25 (m, 1H), 4.02-4.00 (m, 2H), 3.58-3.53 (m, 2H), 3.35 (s, 3H), 2.94-2.87 (m, 2H), 2.30-2.21 (m, 1H), 1.89-1.81 (m, 6H), 1.46 (s, 3H), 0.77 (t, J=7.2 Hz, 3H). LCMS R_(T)=0.79 min; m/z=454.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=454.2.

Example 237 WX Method YYYY

1-benzyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 6-amino-4-methyl-2-tetrahydropyran-4-yl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.08 mmol), 1-benzyltriazole-4-carboxylic acid (16 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethyl propane-1,3-diamine hydrochloride (18 mg, 0.11 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (28-38% acetonitrile in water and 0.05% ammonia hydroxide) to afford 1-benzyl-N-(4-methyl-5-oxo-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,3-triazole-4-carboxamide (17 mg, 49.3%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 7.37-7.32 (m, 5H), 6.18 (s, 1H), 5.63 (s, 2H), 4.53-4.48 (m, 1H), 4.34-4.32 (m, 1H), 4.26-4.17 (m, 1H), 4.01-3.98 (m, 2H), 3.57-3.51 (m, 2H), 3.33 (s, 3H), 2.88-2.82 (m, 2H), 2.28-2.21 (m, 1H), 1.87-1.76 (m, 4H). LCMS R_(T)=1.72 min; m/z=450.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.72 min, ESI+ found [M+H]=450.1.

Example 238 WX Method V

(S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

Step 1: methyl 5-(prop-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (375 mg, 1.46 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (54 mg, 0.07 mmol), potassiumisopropenyltrifluoroborate (433 mg, 2.93 mmol) and cesium carbonate (1193 mg, 3.66 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated at 120° C. for 45 min under microwave conditions. After cooled, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl 5-(prop-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (130 mg, 41%) as a white solid:

LCMS R_(T)=0.769 min; m/z=217.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.769 min, ESI+ found [M+H]=217.8.

Step 2: methyl 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-(prop-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (130 mg, 0.60 mmol) and 10% palladium on carbon (64 mg, 0.60 mmol) in methanol (15 mL) was hydrogenated (15 psi) at 25° C. for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure affording crude methyl 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (100 mg, 76%) as colorless oil: LCMS R_(T)=0.765 min; m/z=219.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.765 min, ESI+ found [M+H]=219.9.

Step 3: 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid

A mixture of methyl 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (50 mg, 0.23 mmol) and lithium hydroxide hydrate (96 mg, 2.28 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred for 20 h at 20° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=4 by addition of hydrochloric acid (1.0 M). The solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (40 mg, 85%) as a white solid:

LCMS R_(T)=0.599 min; m/z=205.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.599 min, ESI+ found [M+H]=205.8.

Step 4: (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A mixture of 5-isopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (40 mg, 0.19 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (41 mg, 0.21 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.23 mmol) and N¹-((ethylimino) methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (45 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (30-60% acetonitrile in water and 0.05% hydrochloric acid) to afford (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (29 mg, 39%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 14.22 (s, 1H), 8.57-8.54 (m, 2H), 8.22 (d, J=1.6 Hz, 1H), 7.53-7.52 (m, 1H), 7.51-7.26 (m, 3H), 4.96-4.91 (m, 1H), 4.69-4.63 (m, 1H), 4.48-4.43 (m, 1H), 3.33 (s, 3H), 3.14-3.07 (m, 1H), 1.26 (d, J=7.2 Hz, 6H): LCMS R_(T)=0.840 min; m/z=380.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.840 min, ESI+ found [M+H]=380.1.

Example 239 WX Method W

(S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

Step 1: methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

To a solution of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (200 mg, 0.78 mmol) in tetrahydrofuran (5 mL) was added triethylamine (158 mg, 1.56 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (195 mg, 1.17 mmol). The reaction was stirred at 25° C. for 20 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude methyl 5-bromo-1-((2-(trimethyl silyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carb oxylate (300 mg, 99%) as yellow oil: LCMS R_(T)=0.999 min; m/z=387.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.999 min, ESI+ found [M+H]=387.8.

Step 2: Cesium 5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (100 mg, 0.26 mmol), cesium carbonate (211 mg, 0.65 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (9 mg, 0.01 mmol) and cyclopropylboronic acid (45 mg, 0.52 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was heated at 120° C. for 60 min under microwave conditions. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude cesium 5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (120 mg, 100%) as a dark solid: LCMS R_(T)=0.866 min; m/z=333.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.866 min, ESI+ found [M+H]=333.9.

Step 3: (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (40 mg, 0.21 mmol), cesium 5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (107 mg, 0.23 mmol) and (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (130 mg, 0.25 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 25° C. for 20 h. The solution was diluted with water (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (25% ethyl acetate in petroleum ether) to afford (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (65 mg, 61%) as a white solid: LCMS R_(T)=0.868 min; m/z=531.0 (M+Na)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.868 min, ESI+ found [M+Na]=531.0.

Step 4: (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

To a solution of (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (60 mg, 0.12 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.09 mL, 1.18 mmol). The mixture was stirred at 25° C. for 1 h and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.05% hydrochloric acid) to afford (S)-5-cyclopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (29 mg, 38%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 14.20 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.52-7.50 (m, 1H), 7.34-7.25 (m, 3H), 4.94-4.90 (m, 1H), 4.68-4.62 (m, 1H), 4.47-4.42 (m, 1H), 3.32 (s, 3H), 2.15-2.09 (m, 1H), 1.04-1.00 (m, 2H), 0.74-0.71 (m, 2H). LCMS R_(T)=0.844 min; m/z=378.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.844 min, ESI+ found [M+H]=378.1.

Example 240 WX Method SS

(S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (47 mg, 0.23 mmol), (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.15 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by SFC (SFC80; Chiralpak OD (100 mm*4.6 mm, 3 um); Supercritical CO₂/ethanol+DEA=5/40; 2.8 ml/min) to afford (S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydr-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (32 mg, 54%) as white solid: ¹H NMR (400 MHz, CD₃OD): δ 7.41-7.31 (m, 5H), 6.43 (s, 1H), 4.73-4.68 (m, 1H), 4.52-4.47 (m, 1H), 4.43-4.38 (m, 3H), 3.38 (s, 3H), 2.93-2.83 (m, 1H), 2.48-2.41 (m, 4H). LCMS R_(T)=1.089 min; m/z=380.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.089 min, ESI+ found [M+H]⁺=380.1

Example 241 WX Method TT

(R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (47 mg, 0.23 mmol), (6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.15 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-50%/0.05% hydrogen chloride in water) to afford (R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (39.8 mg, 67%) as white solid: ¹H NMR (400 MHz, CD₃OD): δ 7.41-7.33 (m, 5H), 6.39 (s, 1H), 4.70-4.63 (m, 1H), 4.49-4.39 (m, 2H), 4.36 (s, 2H), 3.37 (s, 3H), 2.92-2.82 (m, 1H), 2.46-2.41 (m, 1H), 2.39 (s, 3H). LCMS R_(T)=1.090 min; m/z=380.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.090 min, ESI+ found [M+H]-=380.1

Example 242 WX Method UUU

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((2-methylpyridin-4-yl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (150 mg, 0.48 mmol) and potassium carbonate (197 mg, 1.43 mmol) in N,N-dimethylformamide (6 mL) was added 4-(chloromethyl)-2-methylpyridine hydrochloride (102 mg, 0.57 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (methanol 40-70%/0.05% ammonia hydroxide in water) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((2-methylpyridin-4-yl)methyl)-1H-1,2,4-triazole-3-carboxamide (28 mg, 14%): ¹H NMR (400 MHz, CD₃OD) δ 8.66 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.20 (s, 1H), 7.11 (d, J=5.2 Hz, 1H), 6.01 (s, 1H), 5.54 (s, 2H), 4.55-4.51 (m, 1H), 4.32-4.28 (m, 1H), 4.23-4.19 (m, 1H), 2.87-2.80 (m, 1H), 2.51 (s, 3H), 2.28-2.21 (m, 1H), 1.93-1.87 (m, 1H), 0.97-0.90 (m, 2H), 0.77-0.70 (m, 2H). LCMS R_(T)=1.31 min; m/z=421.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.31 min, ESI+ found [M+H]=421.2.

Example 243 WX Method BBBB

(S)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-ethyl-1-m ethyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1S)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (19 mg, 0.09 mmol), (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (20 mg, 0.09 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (20 mg, 0.10 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (14 mg, 0.10 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 0-40%/0.1% ammonium hydroxide in water) to afford (S)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (6.6 mg, 17%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.90 (s, 1H), 6.99-6.84 (m, 2H), 5.22-5.13 (m, 2H), 5.09-5.05 (m, 1H), 4.72-4.68 (m, 1H), 4.55-4.48 (m, 1H), 1.89-1.83 (m, 2H), 1.47 (s, 3H), 0.78 (t, J=7.2 Hz, 3H). LCMS R_(T)=1.09 min; m/z=404.1 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.03% trifluoroacetic over 2 mins) retention time 1.09 min, ESI+ found [M+H]⁺=404.1.

Example 244 WX Method AAAAA

(R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

Step 1: (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-2-nitrophenoxy)propaneic acid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (1.0 g, 4.87 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (234 mg, 9.75 mmol) at 0° C. was added 1,3,5-trifluoro-2-nitrobenzene (863 mg, 4.87 mmol). The reaction mixture was stirred at 15° C. for 16 h and adjusted to pH=4 by addition of hydrochloric acid (2.0 M). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-2-nitrophenoxy)propaneic acid (1.2 g, 68%) as yellow solid, used in the next step without further purification. LCMS R_(T)=0.772 min; m/z=385.1 (M+Na)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.772 min, ESI+ found [M+Na]⁺=385.1.

Step 2: (S)-3-(2-amino-3,5-difluorophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid

A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluoro-2-nitrophenoxy) propaneic acid (1.2 g, 3.31 mmol) and 10% palladium on carbon (353 mg, 0.33 mmol) in methanol (30 mL) was hydrogenated (15 psi) at 15° C. for 3 h. After filtration, the filtrate was concentrated under reduced pressure to afford (S)-3-(2-amino-3,5-difluorophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.8 g, 73%) as a black solid, used in the next step without further purification.

Step 3: (S)-tert-butyl (6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

A mixture of (S)-3-(2-amino-3,5-difluorophenoxy)-2-((tert-butoxycarbonyl)amino) propanoic acid (0.8 g, 2.41 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (463 mg, 2.41 mmol) in N,N-dimethylformamide (20 mL) was stirred at 15° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford (S)-tert-butyl (6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (0.4 g, 53%) as yellow solid: LCMS R_(T)=0.87 min; m/z=258.8 (M−56)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoroacetic over 1.5 mins) retention time 0.817 min, ESI+ found [M−56]⁺=258.8

Step 4: (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride

A mixture of (S)-tert-butyl (6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (0.4 g, 1.27 mmol) and hydrochloric acid (4M in EtOAc, 4.0 mL, 16.0 mmol) in ethyl acetate (10 mL) was stirred at 15° C. for 1 h. The mixture was concentrated under reduced pressure to afford crude (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (300 mg, 94%) as white solid, used in the next step without further purification.

Step 5: (R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (19 mg, 0.09 mmol), (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (20 mg, 0.09 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (20 mg, 0.10 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (14 mg, 0.10 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 0-40%/0.1% ammonium hydroxide in water) to afford (R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-ethyl-1-m ethyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (7.1 mg, 19%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.90 (s, 1H), 6.99-6.84 (m, 2H), 5.17-5.13 (m, 2H), 5.09-5.05 (m, 1H), 4.72-4.68 (m, 1H), 4.55-4.48 (m, 1H), 1.89-1.83 (m, 2H), 1.47 (s, 3H), 0.78 (t, J=7.6 Hz, 3H). LCMS R_(T)=1.09 min; m/z=404.1 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.03% trifluoroacetic over 2 mins) retention time 1.09 min, ESI+ found [M+H]⁺=404.1.

Example 245 WX Method BBBB

(R)—N—((S)-2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (23 mg, 0.11 mmol), 6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (24 mg, 0.14 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (17-47% acetonitrile in water and 0.05% ammonium bicarbonate) to give (R)—N—((S)-2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (15.3 mg, 41%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 7.92 (s, 1H), 6.06 (s, 1H), 5.25-5.21 (m, 2H), 4.63-4.59 (m, 1H), 4.38-4.23 (m, 2H), 3.38 (s, 3H), 3.02-2.93 (m, 1H), 2.31-2.30 (m, 1H), 1.96-1.88 (m, 3H), 1.51 (s, 3H), 1.00-0.98 (m, 2H), 0.84-0.79 (m, 5H). LCMS R_(T)=1.06 min; m/z=410.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.06 min, ESI+ found [M+H]=410.2.

Example 246 WX Method ZZ

1-((4,4-difluorocyclohexyl)methyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (2.4 g, 12.4 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (3.3 g, 18.5 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (170 mg, 1.24 mmol) and 1H-1,2,4-triazole-3-carboxylic acid (1.7 g, 14.8 mmol) in N,N-dimethylformamide (60 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 3% methanol in dichloromethane) to afford N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (2.8 g, 75%) as white solid, used as is in the next step.

Step 2: 1-((4,4-difluorocyclohexyl)methyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 4-(bromomethyl)-1,1-difluorocyclohexane (250 mg, 1.17 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 46-76%/0.05% ammonia hydroxide in water) to afford 1-((4,4-difluorocyclohexyl)methyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxam (40.2 mg, 8%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 6.10 (s, 1H), 4.52-4.49 (m, 1H), 4.29-4.17 (m, 4H), 3.29 (s, 3H), 2.85-2.80 (m, 1H), 2.27-2.22 (m, 4H), 2.20-2.04 (m, 4H), 1.78-1.67 (m, 3H), 1.34-1.27 (m, 2H). LCMS R_(T)=0.751 min; m/z=422.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.751 min, ESI+ found [M+H]=422.1.

Example 247 WX Method AAA

1-(cyclobutylmethyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added (bromomethyl)cyclobutane (258 mg, 1.73 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 42-72%/0.05% ammonia hydroxide in water) to afford 1-(cyclobutylmethyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (50.4 mg, 16%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 6.09 (s, 1H), 4.51-4.48 (m, 1H), 4.29-4.19 (m, 4H), 3.28 (s, 3H), 2.87-2.83 (m, 2H), 2.23-2.04 (m, 4H), 2.05-2.03 (m, 2H), 1.92-1.90 (m, 2H), 1.84-1.80 (m, 2H). LCMS R_(T)=0.736 min; m/z=358.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.736 min, ESI+ found [M+H]=358.1.

Example 248 WX Method BBB

1-((3,3-difluorocyclobutyl)methyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 3-(bromomethyl)-1,1-difluoro-cyclobutane (320 mg, 1.73 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 42-72%/0.05% ammonia hydroxide in water) to afford 1-((3,3-difluorocyclobutyl)methyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (50 mg, 15%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 6.12 (s, 1H), 4.54-4.52 (m, 1H), 4.41 (d, J=6.8 Hz, 2H), 4.32-4.22 (m, 2H), 3.31 (s, 3H), 2.85-2.68 (m, 2H), 2.66-2.64 (m, 2H), 2.48-2.44 (m, 2H), 2.30-2.26 (m, 4H).

LCMS R_(T)=0.715 min; m/z=394.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.715 min, ESI+ found [M+H]=394.1.

Example 249 WX Method DDD

1-(4-chlorobenzyl)-N-(2,4-dimethyl-5-oxo 6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 4-chlorobenzyl bromide (355 mg, 1.73 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 46-76%/0.05% ammonia hydroxide in water) to afford 1-(4-chlorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (60.4 mg, 17%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 7.37-7.32 (m, 4H), 6.32 (s, 1H), 5.46 (s, 2H), 4.63-4.61 (m, 1H), 4.40-4.30 (m, 2H), 3.29 (s, 3H), 2.88-2.82 (m, 1H), 2.38-2.32 (m, 4H).

LCMS R_(T)=0.767 min; m/z=414.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.767 min, ESI+ found [M+H]=414.1.

Example 250 WX Method EEE

N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 1-iodo-3,3,3-trifluoropropane (387 mg, 1.73 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 25-55%/0.05% ammonia hydroxide in water) to afford N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxamide (41.2 mg, 10%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 6.10 (s, 1H), 4.56-4.52 (m, 3H), 4.29-4.20 (m, 2H), 3.29 (s, 3H), 2.90-2.83 (m, 3H), 2.29-2.24 (m, 4H). LCMS R_(T)=0.701 min; m/z=386.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.701 min, ESI+ found [M+H]=386.0.

Example 251 WX Method GGG

1-(cyclopentylmethyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added bromomethylcyclopentane (282 mg, 1.73 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 40-70%/0.05% ammonium hydroxide in water) to afford 1-(cyclopentylmethyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (70.4 mg, 22%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.35-4.15 (m, 4H), 3.34 (s, 3H), 2.91-2.81 (m, 1H), 2.53-2.44 (m, 1H), 2.30-2.23 (m, 4H), 1.70-1.58 (m, 6H), 1.34-1.28 (m, 2H). LCMS R_(T)=1.157 min; m/z=372.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.157 min, ESI+ found [M+H]⁺=372.2.

Example 252 WX Method LL

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

Step 1: 4-bromo-1-oxido-pyridin-1-ium

To a solution of 4-bromopyridine hydrochloride (20.0 g, 102.9 mmol) in water (200 mL) and dichloromethane (300 mL) was added sodium carbonate (16.4 g, 154.3 mmol). The mixture was extracted with dichloromethane (2×200 mL). The combined organic layers were dried over sodium sulfate, and then added 3-chloroperoxybenzoicacid (35.5 g, 205.7 mmol). After addition, the mixture was stirred at 34° C. for 2 h, and then washed with saturated aqueous sodium sulfite (200 mL), saturated aqueous sodium carbonate (200 mL), brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 4-bromo-1-oxido-pyridin-1-ium (10.0 g, 56%) as a white solid, used in the next step without further purification.

Step 2: Methyl 2-(4-bromo-2-pyridyl)acetate

To a solution of 4-bromopyridinen-oxide (5.0 g, 28.7 mmol) in tetrahydrofuran (150 mL) was added 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (10.8 g, 57.5 mmol), bromo[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate (14.7 g, 31.6 mmol) and N,N-diisopropylethylamine (11.1 g, 86.2 mmol) at 25° C. The reaction was heated at 45° C. for 2 h. After cooled, the reaction was poured into water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford methyl 2-(4-bromo-2-pyridyl)acetate (2.6 g, 39%) as yellow oil: ¹H NMR (400 MHz, MeOD) δ 8.33 (d, J=5.6 Hz, 1H), 7.67 (s, 1H), 7.57-7.53 (m, 1H), 3.90-3.80 (m, 2H), 3.71 (s, 3H). LCMS R_(T)=0.474 min; m/z=229.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.474 min, ESI+ found [M+H]=229.8

Step 3: Methyl 5-bromotriazolo[1,5-a]pyridine-3-carboxylate

To a solution of methyl 2-(4-bromo-2-pyridyl) acetate (2.7 g, 11.6 mmol) in acetonitrile (300 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 g, 17.3 mmol) and 4-acetamidobenzenesulfonylazide (2.8 g, 11.6 mmol) at 0° C. After addition, the mixture was allowed to warm to 25° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford methyl 5-bromotriazolo[1,5-a]pyridine-3-carboxylate (2.2 g, 74%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 9.25 (d, J=7.2 Hz, 1H), 8.36 (s, 1H), 7.56 (d, J=6.0 Hz, 1H), 3.93 (s, 3H).

LCMS R_(T)=0.714 min; m/z=255.7 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.714 min, ESI+ found [M+H]=255.7.

Step 4: Methyl 5-[1-(trifluoromethyl)vinyl]triazolo[1,5-a]pyridine-3-carboxylate

A mixture of methyl 5-bromotriazolo[1,5-a]pyridine-3-carboxylate (100 mg, 0.40 mmol), 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride (28 mg, 0.04 mmol), cesium carbonate (254 mg, 0.78 mmol) and 1-(trifluoromethyl) vinylboronic acid hexylene glycol ester (130 mg, 0.58 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was heated at 110° C. for 30 min under microwave conditions. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 35% ethyl acetate in petroleum ether) to afford methyl 5-[1-(trifluoromethyl)vinyl]triazolo[1,5-a]pyridine-3-carboxylate (70 mg, 66%) as a yellow solid: ¹H NMR (400 MHz, MeOD) δ 9.08 (d, J=7.6 Hz, 1H), 8.29 (s, 1H), 7.47-7.43 (m, 1H), 6.36-6.31(m, 2H), 4.00 (s, 3H). LCMS R_(T)=0.812 min; m/z=271.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.812 min, ESI+ found [M+H]=271.8

Step 5: Methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylate

A mixture of methyl 5-[1-(trifluoromethyl)vinyl]triazolo[1,5-a]pyridine-3-carboxylate (60 mg, 0.22 mmol) and 10% palladium on carbon (23 mg, 0.02 mmol) in methanol (5 mL) was hydrogenated (50 psi) at 45° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure affording crude methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylate (47 mg, 77%) as a yellow solid: LCMS R_(T)=0.778 min; m/z=277.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.778 min, ESI+ found [M+H]=277.9

Step 6: 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid

A mixture of methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazolo [1,5-a]pyridine-3-carboxylate (47 mg, 0.17 mmol) and lithium hydroxide hydrate (20 mg, 0.85 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 29° C. for 18 h. After evaporation of the organics under reduced pressure, the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The solid was removed by filtration and the aqueous layer was concentrated under reduced pressure affording crude 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid (25 mg, 56%) as a white solid: LCMS R_(T)=1.560 min; m/z=264.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.04% formic acid over 3 mins) retention time 1.560 min, ESI+ found [M+H]=264.1.

Step 7: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

A mixture of 5-(2,2,2-trifluoro-1-methyl-ethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid (25 mg, 0.09 mmol), (3s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (20 mg, 0.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.11 mmol) in N, N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% ammonia in water) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide (11.5 mg, 27%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=6.4 Hz, 1H), 7.52-7.45 (m, 1H), 7.36-7.19 (m, 3H), 4.90-4.78 (m, 1H), 4.65-4.53 (m, 2H), 4.39 (t, J=8.4 Hz, 1H), 4.31-4.17 (m, 1H), 3.30 (s, 3H), 3.21-3.04 (m, 1H), 2.79-2.59 (m, 2H), 2.35-2.18 (m, 1H), 2.14-1.99 (m, 1H), 1.97-1.77 (m, 1H), 1.16-1.02 (m, 3H). LCMS R_(T)=0.853 min; m/z=438.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.853 min, ESI+ found [M+H]=438.1.

Example 253 WX Method FFF

1-(cyclohexylmethyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (200 mg, 0.69 mmol) and potassium carbonate (287 mg, 2.07 mmol) in N,N-dimethylformamide (5 mL) was added cyclohexylmethyl bromide (245 mg, 1.38 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 50-80%/0.05% ammonium hydroxide in water) to afford 1-(cyclohexylmethyl)-N-(2, 4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (55.5 mg, 21%) as white solid: ¹H NMR (400 MHz, CD₃OD): δ 8.46 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.35-4.18 (m, 2H), 4.11 (d, J=8.0, 2H), 3.34 (s, 3H), 2.91-2.81 (m, 1H), 2.30-2.23 (m, 4H), 1.96-1.91 (m, 1H), 1.76-1.68 (m, 3H), 1.63-1.56 (m, 2H), 1.33-1.19 (m, 3H), 1.06-0.97 (m, 2H). LCMS R_(T)=1.226 min; m/z=386.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.226 min, ESI+ found [M+H]⁺=386.2.

Example 254 WX Method NNN

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (3.6 g, 16.3 mmol), 1H-1,2,4-triazole-3-carboxylic acid (2.2 g, 19.6 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (220 mg, 1.6 mmol) and N′-((ethylimino) methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (4.4 g, 24.5 mmol) in N,N-dimethylformamide (60 mL) was stirred at 25° C. for 12 h. After removed the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 3% methanol in dichloromethane) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (2.6 g, 46%) as white solid: LCMS R_(T)=1.07 min, m/z=316.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3 mins) retention time 1.07 min, ESI+ found [M+H]=316.1

Step 2: N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol) and 4-(bromomethyl)tetrahydropyran (213 mg, 1.19 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (40-70% methyl alcohol in water and 0.05% ammonia hydroxide) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((tetrahydro-2H-pyran-4-yl)meth yl)-1H-1,2,4-triazole-3-carboxamide (46 mg, 14%): ¹H NMR (400 MHz, CD₃OD) δ 8.05 (s, 1H), 6.03 (s, 1H), 4.60-4.56 (m, 2H), 4.34-4.30 (m, 1H), 4.18-4.16 (m, 2H), 4.00-3.94 (m, 2H), 3.44-3.40 (m, 2H), 3.38-3.34 (m, 3H), 2.87-2.86 (m, 1H), 2.28-2.26 (m, 2H), 1.92-1.91 (m, 1H), 1.50-1.41 (m, 2H), 1.39-1.28 (m, 2H), 0.97-0.94 (m, 2H), 0.78-0.75 (m, 2H). LCMS R_(T)=1.57 min, m/z=414.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.57 min, ESI+ found [M+H]=414.2.

Example 255 WX Method OOO

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((4,4-difluorocyclohexyl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol) and 4-(bromomethyl)-1,1-difluorocyclohexane (253 mg, 1.19 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methyl alcohol in water and 0.05% ammonia hydroxide) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((4,4-difluorocyclohexyl)methyl)-1H-1,2,4-triazole-3-carboxamide (28.3 mg, 8%): ¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 6.00 (s, 1H), 4.55-4.50 (m, 1H), 4.29-4.18 (m, 4H), 3.33 (s, 3H), 2.88-2.83 (m, 1H), 2.27-2.22 (m, 1H), 2.05-2.04 (m, 3H), 1.90-1.66 (m, 5H), 1.35-1.32 (m, 2H), 0.95-0.92 (m, 2H), 0.75-0.72 (m, 2H). LCMS R_(T)=1.79 min; m/z=448.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.79 min, ESI+ found [M+H]=448.2.

Example 256 WX Method PPP

1-(cyclobutylmethyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol) and (bromomethyl)cyclobutane (177 mg, 1.19 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methyl alcohol in water and 0.05% ammonia hydroxide) to afford 1-(cyclobutylmethyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (57.2 mg, 18%): ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 6.01 (s, 1H), 4.55-4.50 (m, 1H), 4.34-4.28 (m, 4H), 3.32 (s, 3H), 2.90-2.84 (m, 2H), 2.26-2.08 (m, 1H), 1.95-1.93 (m, 2H), 1.92-1.83 (m, 5H), 0.99-0.93 (m, 2H), 0.76-0.73 (m, 2H). LCMS R_(T)=1.73 min; m/z=384.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.73 min, ESI+ found [M+H]=384.2.

Example 257 WX Method QQQ

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol) and 4-fluorobenzyl chloride (172 mg, 1.19 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (50-80% methyl alcohol in water and 0.05% ammonia hydroxide) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (52.4 mg, 15%): ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.31-7.27 (m, 2H), 7.10-7.06 (m, 2H), 5.78 (s, 1H), 5.36 (s, 2H), 4.78-4.74 (m, 1H), 4.40-4.34 (m, 1H), 4.13-4.06 (m, 1H), 3.34 (s, 3H), 3.19-3.14 (m, 1H), 2.04-2.01 (m, 1H), 2.00-1.88 (m, 1H), 0.95-0.93 (m, 2H), 0.75-0.74 (m, 2H). LCMS R_(T)=1.76 min; m/z=424.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.76 min, ESI+ found [M+H]=424.2.

Example 258 WX Method RRR

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL), was added potassium carbonate (329 mg, 2.38 mmol) and 1-iodo-3,3,3-trifluoropropane (266 mg, 1.19 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (50-70% methyl alcohol in water and 0.05% ammonia hydroxide) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][,3]diazepin-6-yl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxamide (42.7 mg, 13%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.55 (d, J=7.6 Hz, 1H), 6.05 (s, 1H), 4.52 (t, J=6.8 Hz, 2H), 4.31-4.22 (m, 2H), 4.20-4.07 (m, 1H), 3.18 (s, 3H), 3.00-2.90 (m, 2H), 2.57-2.55 (m, 1H), 2.33-2.30 (m, 1H), 1.85-1.81 (m, 1H), 0.85-0.82 (m, 2H), 0.66-0.63 (m, 2H). LCMS R_(T)=1.65 min; m/z=412.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.65 min, ESI+ found [M+H]=412.1.

Example 259 WX Method SSS

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((6-methylpyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (329 mg, 2.38 mmol) and 2-(bromomethyl)-6-methylpyridine (221 mg, 1.19 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (45-75% methyl alcohol in water and 0.05% ammonia hydroxide) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((6-methylpyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxamide (36.6 mg, 11%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.52 (d, J=7.6 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.03 (s, 1H), 5.51 (s, 2H), 4.34-4.19 (m, 2H), 4.12-4.07 (m, 1H), 3.17 (s, 3H), 2.54-2.52 (m, 1H), 2.40 (s, 3H), 2.35-2.30 (m, 1H), 1.88-1.80 (m, 1H), 0.84-0.82 (m, 2H), 0.65-0.62 (m, 2H). LCMS R_(T)=1.46 min; m/z=421.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.46 min, ESI+ found [M+H]=421.2.

Example 260 WX Method XXX

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(cyclopropylmethyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added (bromomethyl)cyclopropane (461 mg, 1.72 mmol) and potassium carbonate (358 mg, 2.59 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (methanol 40-70%/0.05% ammonia hydroxide in water) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(cyclopropylmethyl)-1H-1,2,4-tri azole-3-carboxamide (95.9 mg, 33%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.51 (d, J=8.0 Hz, 1H), 6.07 (s, 1H), 4.33-4.22 (m, 2H), 4.12-4.08 (m, 3H), 3.20 (s, 3H), 2.58-2.55 (m, 1H), 2.34-2.30 (m, 1H), 1.86-1.83 (m, 1H), 1.30-1.26 (m, 1H), 0.87-0.84 (m, 2H), 0.68-0.65 (m, 2H), 0.56-0.53 (m, 2H), 0.41-0.38 (m, 2H). LCMS R_(T)=0.73 min; m/z=370.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.73 min, ESI+ found [M+H]=370.1.

Example 261 WX Method WWW

1-(cyclopentylmethyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (200 mg, 0.69 mmol) in N,N-dimethylformamide (5 mL) was added bromomethylcyclopentane (135 mg, 0.83 mmol) and potassium carbonate (287 mg, 2.07 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methanol in water and 0.05% ammonia hydroxide) to afford 1-(cyclopentylmethyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (41.5 mg, 15%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 5.99 (s, 1H), 4.53-4.48 (m, 1H), 4.27-4.17 (m, 4H), 3.28 (s, 3H), 2.85-2.80 (m, 1H), 2.48-2.47 (m, 1H), 2.22-2.10 (m, 1H), 1.88-1.78 (m, 1H), 1.75-1.66 (m, 6H), 1.28-1.25 (m, 2H), 0.93-0.90 (m, 2H), 0.73-0.71 (m, 2H). LCMS R_(T)=0.79 min; m/z=398.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=398.1.

Example 262 WX Method III

1-((2,2-difluorocyclopropyl)methyl)-N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 2-(bromomethyl)-1,1-difluoro-cyclopropane (177 mg, 1.04 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC (methanol 40-70%/0.05% ammonia hydroxide in water) to afford 1-((2,2-difluorocyclopropyl)methyl)-N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (62.6 mg, 19%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 6.10 (s, 1H), 4.55-4.43 (m, 2H), 4.33-4.20 (m, 3H), 3.29 (s, 3H), 2.87-2.80 (m, 1H), 2.29-2.24 (m, 5H), 1.64-1.60 (m, 1H), 1.48-1.42 (m, 1H). LCMS R_(T)=0.696 min; m/z=380.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.696 min, ESI+ found [M+H]=380.1.

Example 263 WX Method PPPPPP

(1R)—N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (11 mg, 0.05 mmol), 3-amino-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one (10 mg, 0.05 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (12 mg, 0.06 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (9 mg, 0.06 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonia hydroxide in water) to afford (1R)—N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (8 mg, 38%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 5.21-5.16 (m, 2H), 4.87-4.57 (m, 1H), 4.39-4.33 (m, 1H), 4.00-3.96 (m, 1H), 3.34 (s, 3H), 2.78-2.76 (m, 1H), 2.23 (s, 3H), 2.15-2.11 (m, 1H), 1.89-1.83 (m, 2H), 1.47 (s, 3H), 0.80-0.76 (m, 3H). LCMS R_(T)=1.87 min; m/z=384.2 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.87/min, ESI+ found [M+H]=384.2.

Example 264 WX Method UUUU

(3R)-3-ethyl-3-methyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of 6-amino-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (20 mg, 0.08 mmol), (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (16 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (16 mg, 0.12 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (38% to 68% acetonitrile, 0.05% ammonia hydroxide in water) to give (3R)-3-ethyl-3-methyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-c arboxamide (21 mg, 60%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.86-7.80 (m, 3H), 7.43-7.31 (m, 3H), 6.70 (s, 1H), 5.19-5.12 (m, 2H), 4.68-4.36 (m, 3H), 3.42 (s, 3H), 3.02-2.94 (m, 1H), 2.35-2.27 (m, 1H), 1.87-1.82 (m, 2H), 1.45 (s, 3H), 0.78-0.74 (m, 3H). LCMS R_(T)=0.76 min; m/z=446.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.76 min, ESI+ found [M+H]=446.1.

Example 265 WX Method VVVV

(3S)-3-ethyl-3-methyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of 6-amino-4-methyl-2-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), (1S)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (24 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (38% to 68% acetonitrile, 0.05% ammonia hydroxide in water) to give (3S)-3-ethyl-3-methyl-N-(4-methyl-5-oxo-2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-c arboxamide (19.2 mg, 36.2%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.86-7.80 (m, 3H), 7.43-7.31 (m, 3H), 6.70 (s, 1H), 5.19-5.12 (m, 2H), 4.68-4.36 (m, 3H), 3.42 (s, 3H), 3.02-2.94 (m, 1H), 2.35-2.29 (m, 1H), 1.87-1.82 (m, 2H), 1.45 (s, 3H), 0.78-0.74 (m, 3H). LCMS R_(T)=0.75 min; m/z=446.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.75 min, ESI+ found [M+H]=446.1.

Example 266 WX Method UU

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-m ethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of 1-methyl-1-(2,2,2-trifluoroethyl)-3H-furo[3,4-c]pyridine-6-carboxylic acid (48 mg, 0.19 mmol), (6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.15 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (25 mg, 0.19 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (38 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 31-61%/0.05% ammonium hydroxide in water) to give N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (57.6 mg, 84%) as light red solid: ¹H NMR (400 MHz, CD₃OD): δ 8.61 (s, 1H), 8.03 (s, 1H), 6.13 (s, 1H), 5.20 (s, 2H), 4.63-4.57 (m, 1H), 4.35-4.24 (m, 2H), 3.35 (s, 3H), 2.92-2.81 (m, 3H), 2.32-2.25 (m, 4H), 1.57 (s, 3H). LCMS R_(T)=1.234 min; m/z=438.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.234 min, ESI+ found [M+H]⁺=438.2.

Example 267 WX Method A

1-cyclopropyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

Step 1: 6-chloro-1-cyclopropyl-1-methylfuro[3,4-c]pyridin-3(1H)-one

To a mixture of 2,2,6,6-tetramethylpiperidine (54.0 g, 381 mmol) in tetrahydrofuran (500 mL) was added n-butyllithium (203 mL, 508 mmol, 2.5 M in tetrahydrofuran) at −78° C. After stirring at −78° C. for 40 min, 6-chloronicotinic acid (20.0 g, 127 mmol) in tetrahydrofuran (200 mL) was added into the mixture and stirred for 2 h at −78° C. 1-cyclopropylethanone (107.0 g, 1269 mmol) was added dropwise into the mixture at −78° C. The reaction was allowed warm to 25° C. and stirred for 16 h. The reaction was quenched by addition of saturated aqueous ammonium chloride and acidified to pH=4 by using hydrochloric acid (2.0 M). The reaction was extracted with ethyl acetate (3×300 mL). The organics were washed with water (2×100 mL), brine (100 mL). The combined organic layers were dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization with ethyl acetate (60 mL) affording 6-chloro-1-cyclopropyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (24.0 g, 84%) as a white solid, used as is in the next step.

Step 2: 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol

To a mixture of 6-chloro-1-cyclopropyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (24.0 g, 107 mmol) in toluene (500 mL) was added diisobutylaluminum hydride (236 mL, 236 mmol, 1.0 M in toluene) and then stirred for 2 h at −78° C. The mixture was quenched by addition of saturated aqueous ammonium chloride at −78° C. and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure affording crude 6-chloro-1-cyclopropyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (23.0 g, 95%) as colourless oil, used as is in the next step.

Step 3: 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine

To a mixture of 6-chloro-1-cyclopropyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol affording (23.0 g, 102 mmol) and 2,2,2-trifluoroacetic acid (58.1 g, 510 mmol) in dichloromethane (100 mL) was added triethylsilane (59.3 g, 510 mmol) at 0° C. After addition, the mixture was stirred for 2 h and then adjusted to pH=8 by additional of 5% aqueous sodium hydroxide. The mixture was concentrated to dryness under reduced pressure. The residue was taken up in ethyl acetate (200 mL). The organics were washed with water (2×100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 100% petroleum ether) affording 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine (17.0 g, 79.6%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 7.14 (s, 1H), 5.07-4.99 (m, 2H), 1.47 (s, 3H), 1.18-1.16 (m, 1H), 0.52-0.29 (m, 4H).

Step 4: methyl 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate

A mixture of 6-chloro-1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine (5.0 g, 24 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride (1.7 g, 2.4 mmol) in methanol (100 mL) was stirred at 80° C. under carbonic oxide atmosphere (25 psi) for 16 h. The reaction was filtrated and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) affording 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (5.3 g, 95%) as colorless oil: LCMS R_(T)=0.65 min; m/z=233.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.65 min, ESI+ found [M+H]=233.8.

Step 5: 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid

A mixture of methyl 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (5.3 g, 23.0 mmol) and lithium hydroxide (5.4 g, 227.0 mmol) in tetrahydrofuran (50 mL) and water (50 mL) was stirred at 25° C. for 16 h. The mixture was adjusted to pH=6 by addition of hydrochloric acid (1.0 M). The resulting solution was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (3.6 g, 72.3%) as a white solid: ¹H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 7.98 (s, 1H), 5.13-5.05 (m, 2H), 1.52 (s, 3H), 1.34-1.27 (m, 1H), 0.50-0.30 (m, 4H).

Step 6: 1-cyclopropyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (30 mg, 0.16 mmol), 1-cyclopropyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (34 mg, 0.16 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (45 mg, 0.23 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.23 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The mixture was concentrated to dryness under reduced pressure and the residue was purified by RP-HPLC affording 1-cyclopropyl-1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydro benzo[b][1,4]oxazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (24 mg, 38%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.95 (s, 1H), 7.47-7.28 (m, 4H), 5.17-5.03 (m, 3H), 4.69-4.65 (m, 1H), 4.45-4.40 (m, 1H), 3.45 (s, 3H), 1.52 (s, 3H), 1.31-1.26 (m, 1H), 0.50-0.28 (m, 4H). LCMS R_(T)=0.76 min; m/z=394.0 (M+H)⁺.

Example 268 WX Method CCC

N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 4-fluorobenzyl bromide (327 mg, 1.73 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 46-76%/0.05% ammonia hydroxide in water) to afford N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (43.7 mg, 13%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.53 (d, J=8.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.23-7.19 (m, 2H), 6.12 (s, 1H), 5.47 (s, 2H), 4.32-4.26 (m, 2H), 4.12-4.09 (m, 1H), 3.21 (s, 3H), 2.50-2.44 (m, 2H), 2.16 (s, 3H).

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.748 min, ESI+ found [M+H]=398.1.

Example 269 WX Method VVV

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((3,3-difluorocyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) and potassium carbonate (329 mg, 2.38 mmol) in N,N-dimethylformamide (5 mL) was added 3-(bromomethyl)-1,1-difluoro-cyclobutane (293 mg, 1.59 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (47-77% methanol in water and 0.05% ammonia) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((3,3-difluorocyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 12%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 8.01 (d, J=6.4 Hz, 1H), 5.76 (s, 1H), 4.76-4.73 (m, 1H), 4.39-4.30 (m, 3H), 4.11-4.05 (m, 1H), 3.33 (s, 3H), 3.20-3.12 (m, 1H), 2.78-2.70 (m, 3H), 2.39-2.33 (m, 2H), 1.90-1.87 (m, 2H), 0.94-0.91 (m, 2H), 0.75-0.72 (m, 2H). LCMS R_(T)=0.95 min; m/z=420.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.95 min, ESI+ found [M+H]=420.2.

Example 270 WX Method HHH

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-(4-fluorophenyl)ethyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: (S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide and (R)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (2.8 g, 9.8 mmol) was separated by chiral SFC (SFC80; Chiralpak OD (150 mm*4.6 mm, 3 um); Supercritical CO₂/MeOH+NH₃.H₂O=20/20; 2.5 ml/min) to afford:

(S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2, 4-triazole-3-carboxamide (Peak 1, R_(T)=3.259 min) (1.2 g, 40%); (R)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2, 4-triazole-3-carboxamide (Peak 2, R_(T)=3.846 min) (1.5 g, 54%).

Step 2: N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-(4-fluorophenyl)ethyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added 1-(1-bromomethyl)-4-fluorobenzene (263 mg, 1.30 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC (methanol 50-80%/0.05% ammonia hydroxide in water) to afford N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-(4-fluorophenyl)ethyl)-1H-1,2,4-triazole-3-carboxamide(21.2 mg, 6%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.53 (d, J=7.6 Hz, 1H), 7.40-7.37 (m, 2H), 7.22-7.18 (m, 2H), 6.13 (s, 1H), 5.86-5.81 (m, 1H), 4.32-4.25 (m, 2H), 4.12-4.07 (m, 1H), 3.21 (s, 3H), 2.67-2.50 (m, 2H), 2.16 (s, 3H), 1.84 (d, J=7.2 Hz, 3H).

LCMS R_(T)=0.759 min; m/z=412.3 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.759 min, ESI+ found [M+H]=412.3.

Example 271 WX Method KKK

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.86 mmol) and potassium carbonate (358 mg, 2.59 mmol) in N,N-dimethylformamide (5 mL) was added (1-bromoethyl)benzene (240 mg, 1.3 mmol) and. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC (methanol 50-80%/0.05% ammonia hydroxide in water) to afford N—((S)-2,4-dimethyl-5-oxo-5, 6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide (24.8 mg, 7%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.53 (d, J=8.0 Hz, 1H), 7.38-7.30 (m, 5H), 6.13 (s, 1H), 5.84-5.78 (m, 1H), 4.33-4.23 (m, 2H), 4.12-4.09 (m, 1H), 3.21 (s, 3H), 2.59-2.57 (m, 1H), 2.37-2.34 (m, 1H), 2.16 (s, 3H), 1.85 (d, J=7.2 Hz, 3H). LCMS R_(T)=0.758 min, m/z=394.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.758 min, ESI+ found [M+H]=394.1.

Example 272 WX Method FFFFF

(S)-1-(2,3-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(2,3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (26 mg, 0.11 mmol), (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium bicarbonate in water) to give (S)-1-(2,3-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (27.9 mg, 71%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 7.29-7.26 (m, 1H), 7.18-7.15 (m, 2H), 5.59 (s, 2H), 4.43-4.38 (m, 1H), 4.24-4.18 (m, 2H), 3.30 (s, 3H), 2.78-2.70 (m, 1H), 2.19 (m, 4H), 2.00 (s, 3H). LCMS R_(T)=0.972 min; m/z=430.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.972 min, ESI+ found [M+H]=430.2.

Example 273 WX Method GGGGG

(S)-1-(3,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (26 mg, 0.11 mmol), (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium bicarbonate in water) to give (S)-1-(3,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (31.3 mg, 80%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.32-7.24 (m, 2H), 7.18-7.17 (m, 1H), 5.45 (s, 2H), 4.39-4.39 (m, 1H), 4.24-4.18 (m, 2H), 3.30 (s, 3H), 2.81-2.73 (m, 1H), 2.20-2.16 (m, 4H), 2.00 (s, 3H). LCMS R_(T)=0.98 min; m/z=430.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.98 min, ESI+ found [M+H]=430.2.

Example 274 WX Method DDDDD

(S)-1-benzyl-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1, 5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (1-benzyl-1,2,4-triazole-3-carboxylic acid (22.1 mg, 0.11 mmol), (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium bicarbonate in water) to give (S)-1-benzyl-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (23.5 mg, 65%) as white solid. ¹¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.38-7.32 (m, 5H), 5.46 (s, 2H), 4.44-4.39 (m, 1H), 4.24-4.18 (m, 2H), 3.30 (s, 3H), 2.81-2.73 (m, 1H), 2.21-2.18 (m, 4H), 2.00 (s, 3H). LCMS R_(T)=0.94 min; m/z=394.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.94 min, ESI+ found [M+H]=394.2.

Example 275 WX Method VV

(R)—N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (38 mg, 0.19 mmol), (6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.15 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (25 mg, 0.19 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (38 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give (R)—N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (25.5 mg, 43%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.87 (s, 1H), 6.13 (s, 1H), 5.21-5.16 (m, 2H), 4.59-4.55 (m, 1H), 4.33-4.24 (m, 2H), 3.35 (s, 3H), 2.95-2.88 (m, 1H), 2.29-2.22 (m, 4H), 1.89-1.83 (m, 2H), 1.47 (s, 3H), 0.77 (t, J=7.6 Hz, 3H). LCMS R_(T)=1.197 min; m/z=384.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.197 min, ESI+ found [M+H]-=384.2.

Example 276 WX Method CCCCC

(R)-1-ethyl-1-methyl-N—((S)-2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

Step 1: N-(4,5-dimethyl-1H-pyrazol-3-yl)formamide

A solution of 4,5-dimethyl-1H-pyrazol-3-amine (15.0 g, 135.0 mmol) in formic acid (75 mL) was heated to 110° C. for 3 h in a sealed vessel. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) to afford N-(4,5-dimethyl-1H-pyrazol-3-yl)formamide (15.0 g, 80%) as an off-white solid, used in the next step without further purification.

Step 2: N-4,5-trimethyl-1H-pyrazol-3-amine

To a solution of N-(5-methyl-1H-pyrazol-3-yl)formamide (15.0 g, 107.8 mmol) in tetrahydrofuran (500 mL) was slowly added lithium aluminum hydride (8.2 g, 215.2 mmol) at 0° C. After addition, the reaction mixture was allowed to warm to 25° C. and stirred for 16 h. The reaction was quenched by addition of solid sodium sulfate decahydrate and stirred at 25° C. for 30 mins. The resulting mixture was diluted with ethyl acetate (200 mL), filtered through celite, and concentrated under reduced pressure to afford N-4,5-trimethyl-1H-pyrazol-3-amine (14.0 g, 104%) as yellow oil, used as is in the next step.

Step 3: 4-chloro-N-(3,4-dimethyl-1H-pyrazol-5-yl)-N-methylbutanamide

A solution of N-4,5-trimethyl-1H-pyrazol-3-amine (14.0 g, 111.8 mmol) in 4-chlorobutanoyl chloride (30.0 mL, 295.0 mmol) was heated to 60° C. for 2 h. After cooled, methanol (30 mL) was added carefully. The mixture was stirred at 20° C. for another 1 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 4-chloro-N-(3,4-dimethyl-1H-pyrazol-5-yl)-N-methylbutanamide (18.0 g, 70%) as an orange oil: LCMS R_(T)=1.08 min; m/z=230.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.08 min, ESI+ found [M+H]=230.1.

Step 4: 2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 4-chloro-N-(3,4-dimethyl-1H-pyrazol-5-yl)-N-methylbutanamide (18.0 g, 78.4 mmol) in N,N-dimethylformamide (200 mL) was added cesium carbonate (51.1 g, 156.7 mmol), and the resulting suspension was stirred at 20° C. for 16 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (11.0 g, 73%) as colorless oil: LCMS R_(T)=0.57 min; m/z=193.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.57 min, ESI+ found [M+H]=193.9.

Step 5: 6-iodo-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (2.0 g, 10.4 mmol) in dichloromethane (50 mL) was added N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (7.2 g, 62.1 mmol) followed by iodotrimethylsilane (12.4 g, 62.1 mmol) at −15° C. The resulting solution was stirred 2 h at −15° C., and iodine (7.9 g, 31.1 mmol) was added in one portion. Stirring at −15° C. was continued for 2 h, and the reaction mixture was quenched by addition of saturated sodium bisulfite (100 mL). The mixture was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give 6-iodo-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a brown solid (230 g, 70%) as yellow oil, used in the next step as is.

Step 6: 6-azido-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5 (6H)-one

To a solution of 6-iodo-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (2.0 g, 6.3 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (611.1 mg, 9.4 mmol). The reaction mixture was stirred at 20° C. for 2 hand then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give 6-azido-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.35 g, 92%) as a pale orange oil: LCMS R_(T)=0.64 min; m/z=235.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.64 min, ESI+ found [M+H]=235.1.

Step 7: (S)-6-amino-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one and (R)-6-amino-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 6-azido-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.4 g, 5.8 mmol) and 10% palladium on carbon (613 mg, 0.58 mmol) was hydrogenated (50 psi) at 25° C. for 10 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 6-amino-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.3 g, 104%) as colorless oil. Then the product was separated by chiral SFC to afford:

(S)-6-amino-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (Peak 1, Retention time: 3.19 min) (580 mg, 44.6% yield); (R)-6-amino-2,3,4-trimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (Peak 2, Retention time: 3.66 min) (500 mg, 38% yield); SFC condition: Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C. Wavelength: 220 nm.

Step 8: (R)-1-ethyl-1-methyl-N—((S)-2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (23 mg, 0.11 mmol), (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium bicarbonate in water) to give (R)-1-ethyl-1-methyl-N—((S)-2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-c arboxamide (16.6 mg, 45.5% yield) as white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.86 (s, 1H), 5.20-5.12 (m, 2H), 4.48-4.44 (m, 1H), 4.26-4.21 (m, 2H), 3.34 (s, 3H), 2.87-2.81 (m, 1H), 2.19-2.16 (m, 4H), 2.02 (s, 3H), 1.87-1.82 (m, 2H), 1.46 (s, 3H), 0.76 (t, J=7.6 Hz, 3H). LCMS R_(T)=1.022 min; m/z=398.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.022 min, ESI+ found [M+H]=398.2.

Example 277 WX Method R

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

Step 1: tert-butyl 2-(4-(perfluoroethyl)pyridin-2-yl)acetate

To a stirred mixture of 2-chloro-4-(1,1,2,2,2-pentafluoroethyl)pyridine (100 mg, 0.43 mmol), tert-butyl acetate (37 mg, 0.32 mmol) and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (30 mg, 0.04 mmol) in toluene (4 mL) was added lithium bis(trimethylsilyl)amide (1.0 M, 0.86 mL, 0.86 mmol) dropwise at 0° C. under nitrogen. After addition, the reaction was stirred at 0° C. for 30 min, then allowed to warm to 25° C. for 12 h. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (10% ethyl acetate in petroleum ether) affording tert-butyl 2-(4-(perfluoroethyl)pyridin-2-yl)acetate (10 mg, 7.4%) as yellow oil, used as is in the next step.

Step 2: tert-butyl 5-(1,1,2,2,2-pentafluoroethyl)triazolo[1,5-a]pyridine-3-carboxylate

A mixture of tert-butyl 2-(4-(perfluoroethyl)pyridin-2-yl)acetate (80 mg, 0.26 mmol), 4-acetamidobenzene sulfonylazide (68 mg, 0.28 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (74 mg, 0.49 mmol) in acetonitrile (5 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (20% ethyl acetate in petroleum ether, R_(f)=0.5) to afford tert-butyl 5-(1,1,2,2,2-pentafluoroethyl)triazolo[1,5-a]pyridine-3-carboxylate (30 mg, 35%) as a white solid: LCMS R_(T)=0.916 min; m/z=281.8 (M+H-56)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 min) retention time 0.916 min, ESI+ found [M+H-56]+=281.8

Step 3: tert-butyl 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylate

A mixture of tert-butyl 5-(1,1,2,2,2-pentafluoroethyl)triazolo[1,5-a]pyridine-3-carboxylate (30 mg, 0.09 mmol) and 10% palladium on carbon (10 mg, 0.09 mmol) in methanol (10 mL) was hydrogenated (35 psi) at 25° C. for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 5-(1,1,2,2,2-pentafluoroethyl)-,5,6,7-tetrahydrotriaazolo[1,5-a]pyridine-3-carboxylate (30 mg, 98%) as a gray solid: LCMS R_(T)=0.873 min; m/z=285.9 (M+H-56)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 min) retention time 0.873 min, ESI+ found [M+H-56]+=285.9

Step 4: 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid

To a solution of tert-butyl 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazolo [1,5-a]pyridine-3-carboxylate (30 mg, 0.09 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (1 mL, 13.4 mmol) at 25° C. The reaction mixture was stirred for 12 h and then concentrated under reduced pressure affording crude 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazzolo[,5-a]pyridine-3-carboxylic acid (30 mg, 119%) as colorless oil: LCMS R_(T)=0.718 min; m/z=286.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 min) retention time 0.718 min, ESI+ found [M+H]=286.1

Step 5: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide

A mixture of 5-(1,1,2,2,2-pentafluoroethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine-3-carboxylic acid (30 mg, 0.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.23 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (47 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% FA in water) to afford N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(perfluoroethyl)-4,5, 6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxamide (8.5 mg, 18%) as a white solid:

¹H NMR (400 MHz, CD₃OD) δ 7.46-7.40 (m, 1H), 7.36-7.26 (m, 2H), 7.26-7.20 (m, 1H), 5.00-4.97 (m, 1H), 4.72-4.68 (m, 1H), 4.62-4.57 (m, 1H), 4.43-4.39 (m, 1H), 4.38-4.29 (m, 1H), 3.54-3.45 (m, 1H), 3.42 (s, 3H), 3.05-2.93 (m, 2H), 2.48-2.44 (m, 1H), 2.19-2.07 (m, 1H). LCMS R_(T)=0.864 min; m/z=460.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 min) retention time 0.864 min, ESI+ found [M+H]=460.1.

Example 278 WX Method YYY

N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((6-methylpyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added 5-(bromomethyl)-2-methylpyridine (636 mg, 1.72 mmol) and potassium carbonate (358 mg, 2.59 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (methanol 40-70%/0.05% ammonia hydroxide in water) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((6-methylpyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxamide (33 mg, 10%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.47 (d, J=1.6 Hz, 1H), 7.75-7.73 (m, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.00 (s, 1H), 5.51 (s, 2H), 4.54-4.49 (m, 1H), 4.29-4.15 (m, 2H), 3.31 (s, 3H), 2.86-2.80 (m, 1H), 2.53 (s, 3H), 2.28-2.23 (m, 1H), 1.92-1.87 (m, 1H), 0.95-0.92 (m, 2H), 0.75-0.72 (m, 2H). LCMS R_(T)=0.53 min; m/z=421.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.53 min, ESI+ found [M+H]=421.1.

Example 279 WX Method X

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

Step 1: methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

To a solution of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (500 mg, 1.95 mmol) in dichloromethane (20 mL) was added pyridin-1-ium 4-methylbenzenesulfonate (49 mg, 0.20 mmol) and 3,4-dihydro-2h-pyran (329 mg, 3.91 mmol). After addition, the mixture was stirred at 60° C. for 6 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (25 mL). The separated organic layer was washed with saturated aqueous sodium bicarbonate (10 mL), dried over sodium sulfate and concentrated to afford crude methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (600 mg, 90%) as a yellow solid: LCMS R_(T)=0.811 min; m/z=340.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.811 min, ESI+ found [M+H]=340.0.

Step 2: methyl 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (300 mg, 0.88 mmol), cuprous iodide (8 mg, 0.04 mmol), (1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (13 mg, 0.09 mmol) and sodium iodide (264 mg, 1.76 mmol) in 1,4-dioxane (3 mL) was heated at 110° C. for 20 h in a sealed tube. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford methyl 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (330 mg, 97%) as a white solid: LCMS R_(T)=0.824 min; m/z=388.0 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% formic acid over 2.0 mins) retention time 0.824 min, ESI+ found [M+H]=388.0.

Step 3: methyl 5-trifluoromethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (220 mg, 0.57 mmol), cuprous iodide (108 mg, 0.57 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (218 mg, 1.14 mmol) in N,N-dimethylacetamide (2.5 mL) was heated at 100° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford methyl 5-trifluoromethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (100 mg, 53%) as a white solid: LCMS R_(T)=0.884 min, m/z=330.0[M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.884 min, ESI+ found [M+H]=330.0.

Step 4: methyl 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-trifluoromethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (80 mg, 0.24 mmol) and trifluoroacetic acid (277 mg, 2.43 mmol) in dichloromethane (5 mL) was stirred at 25° C. for 2 h. The solvent was removed under reduced pressure to afford crude methyl 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (50 mg, 84%) as a yellow solid: LCMS R_(T)=0.699 min; m/z=246.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.699 min, ESI+ found [M+H]=246.0.

Step 5: 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid

A mixture of methyl 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (50 mg, 0.20 mmol) and lithium hydroxide hydrate (86 mg, 2.04 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 20° C. for 20 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted pH=4 by addition of hydrochloric acid (1.0 M). The solution was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (40 mg, 85%) as a white solid: LCMS R_(T)=0.612 min; m/z=232.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.612 min, ESI+ found [M+H]=232.1.

Step 6: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A mixture of 5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (40 mg, 0.19 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (37 mg, 0.19 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (40 mg, 0.21 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (28 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (40-70% acetonitrile in water and 0.05% hydrochloric acid) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (19 mg, 25%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 8.69 (d, J=1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.35-7.26 (m, 3H), 4.98-4.93 (m, 1H), 4.71-4.66 (m, 1H), 4.48-4.44 (m, 1H), 3.33 (s, 3H). LCMS R_(T)=0.848 min; m/z=406.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.848 min, ESI+ found [M+H]=406.0.

Example 280 WX Method HHHHH

(S)-1-(2,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (28 mg, 0.12 mmol), (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N3-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (MeOH 50-80%/0.05% ammonia hydroxide in water) to afford (S)-1-(2,4-difluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (30 mg, 73%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.49-7.43 (m, 1H), 7.05-6.98 (m, 2H), 5.52 (s, 2H), 4.44-4.40 (m, 1H), 4.24-4.19 (m, 2H), 3.31 (s, 3H), 2.81-2.73 (m, 1H), 2.22-2.19 (s, 4H), 2.01 (s, 3H). LCMS R_(T)=0.76 min; m/z=430.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.76 min, ESI+ found [M+H]=430.1.

Example 281 WX Method IIIII

(S)-1-(4-fluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1, 3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (24 mg, 0.11 mmol), (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (MeOH 20-50%/0.05% ammonia hydroxide in water) to afford (S)-1-(4-fluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (10.2 mg, 27%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.42 (d, J=7.6 Hz, 1H), 7.40-7.36 (m, 2H), 7.23-7.19 (m, 2H), 5.47 (s, 2H), 4.25-4.09 (m, 3H), 3.19 (s, 3H), 2.50-2.49 (m, 1H), 2.25-2.10 (m, 1H), 2.09 (s, 3H), 1.93 (s, 3H). LCMS R_(T)=0.76 min; m/z=412.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.76 min, ESI+ found [M+H]=412.1.

Example 282 WX Method HHHH

(S)-5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3,4-oxadiazole-2-carboxamide

A mixture of 5-benzyl-1,3,4-oxadiazole-2-carboxylic acid (28 mg, 0.14 mmol), (6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (methanol 45-75%/0.05% ammonium hydroxide in water) to afford (S)-5-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,3,4-oxadiazole-2-carboxamide (13.9 mg, 37%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.35-7.28 (m, 5H), 6.02 (s, 1H), 4.50-4.45 (m, 1H), 4.33-4.21 (m, 4H), 3.32 (s, 3H), 2.81-2.75 (m, 1H), 2.35-2.31 (m, 1H), 1.92-1.88 (m, 1H), 0.95-0.92 (m, 2H), 0.75-0.72 (m, 2H). LCMS R_(T)=1.238 min; m/z=407.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.238 min, ESI+ found [M+H]⁺=407.1.

Example 283 WX Method KKKKK

1-benzyl-N-((6S)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: butyl 2,2-difluorocyclopropanecarboxylate

A solution of 2,2-difluorocyclopropanecarboxylic acid (30.0 g, 245.8 mmol) in acetonitrile (300 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (37.4 g, 245.8 mmol) and 1-iodobutane (49.8 g, 270.3 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 12 h and then quenched by addition of water (300 mL). The solution was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to give crude butyl 2, 2-difluorocyclopropanecarboxylate (30.0 g, 69%) as a yellow oil, used in the next step without further purification.

Step 2: 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile

To a solution of acetonitrile (10 mL, 185.2 mmol) in tetrahydrofuran (500 mL) was added n-butyllithium (2.5 M, 74.0 mL, 185.2 mmol) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes, then butyl 2, 2-difluorocyclopropanecarboxylate (30.0 g, 168.4 mmol) was added. The mixture was then allowed to warm to 25° C. and stirred for another 2 h. The reaction mixture was concentrated under reduced pressure to give crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile (20.0 g, 82%) as a yellow oil, used in the next step without further purification.

Step 3: 5-(2, 2-difluorocyclopropyl)-1H-pyrazol-3-amine

A mixture of 3-(2,2-difluorocyclopropyl)-3-oxo-propanenitrile (20.0 g, 137.8 mmol) and hydrazine hydrate (50 mL, 85%) in 2-methyl-1-propanol (100 mL) was heated to 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to give 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine (16.0 g, 73%) as a yellow oil. LCMS R_(T)=0.93 min; m/z=160.1 (M+H)⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3 minutes) retention time 0.93 min, ESI+ found [M+H]=160.1.

Step 4: N-(5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)formamide

A solution of 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine (16.0 g, 100.5 mmol) in formic acid (80 mL) was heated at 110° C. for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]formamide (14.0 g, 74%) as a yellow solid:

LCMS R_(T)=1.35 min; m/z=188.1 (M+H)⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3.0 mins) retention time 1.35 min, ESI+ found [M+H]=188.1.

Step 5: 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine

To a solution of N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]formamide (10.0 g, 53.4 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydride (4.1 g, 106.9 mmol) in small portions at 0° C. The reaction mixture was stirred at 25° C. for another 12 h, and then slowly quenched by addition of water (5 mL), 10% aqueous sodium hydroxide (5 mL). The resulting mixture was filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (7.0 g, 76%) as a colorless oil, used in the next step without further purification.

Step 6: 4-chloro-N-(5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide

A solution of 5-(2,2-difluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (9.0 g, 51.9 mmol) in 4-chlorobutanoyl chloride (20 mL) was stirred for 4 h at 60° C. After cooled, the reaction mixture was slowly quenched by addition of methanol (10 mL). The solvent under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 4-chloro-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (11.0 g, 76%) as a yellow oil: LCMS R_(T)=0.76 min; m/z=277.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.76 min, ESI+ found [M+H]=277.9.

Step 7: 2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 4-chloro-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (11.0 g, 39.6 mmol) and cesium carbonate (25.8 g, 79.2 mmol) in N,N-dimethylformamide (200 mL) was stirred at 25° C. for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane to afford 2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (9.0 g, 94%) as a yellow oil: LCMS R_(T)=2.36 min; m/z=242.1 (M+H)⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 2.36 min, ESI+ found [M+H]=242.1.

Step 8: 2-(2,2-difluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.6 g, 17.5 mmol) in dichloromethane (200 mL) was added tetramethylethylenediamine (20.4 g, 175.4 mmol) and iodotrimethylsilane (35.1 g, 175.4 mmol) at −15° C. The resulting mixture was stirred at −15° C. for 1.5 h and then iodine (22.3 g, 87.7 mmol) was added in one portion. The reaction mixture was stirred at −15° C. for 3 h and then quenched by addition of saturated sodium bisulfite solution (70 mL). The solution was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give 2-(2,2-difluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.6 g, 62%) as a colorless oil, used as is in the next step.

Step 9: 6-azido-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 2-(2,2-difluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (7.2 g, 19.6 mmol) in N,N-dimethylformamide (40 mL) was added sodium azide (1.9 g, 29.4 mmol). The reaction mixture was stirred at 25° C. for 2 h and then poured into ice water (5 mL). The solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 6-azido-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5 (6H)-one (5.0 g, 90%) as a light yellow oil: LCMS R_(T)=2.86 min; m/z=283.1 (M+H)⁺.

LCMS (0 to 30% acetonitrile in water+0.03% ammonium hydroxide over 3.0 mins) retention time 2.86 min, ESI+ found [M+H]=283.1

Step 10: 6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 6-azido-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (5.0 g, 17.7 mmol) in tetrahydrofuran (100 mL) and water (20 mL) was added polymer-bound triphenylphosphine (25 g, −3 mmol/g loading). The mixture was shaken at 25° C. for 16 h and then filtered through a short pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one as a colorless oil (4.5 g, 99%): LCMS R_(T)=1.52 min; m/z=257.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium hydroxide over 3.0 mins) retention time 1.52 min, ESI+ found [M+H]=257.1

Step 11: (S)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1, 3]diazepin-5(6H)-one; (R)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1, 3]diazepin-5(6H)-one; (R)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one and (S)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1, 3]diazepin-5(6H)-one

6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.9 g, 7.7 mmol) was separated by SFC to afford: Peak 1 (Retention time: 2.26 min), tentatively assigned as: (S)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]di azepin-5(6H)-one (380 mg, 20.0% yield); Peak 2 (Retention time: 2.46 min), tentatively assigned as: (R)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(400 mg, 21.0% yield); Peak 3 (Retention time: 2.64 min), tentatively assigned as: (R)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(390 mg, 20.5% yield); Peak 4 (Retention time: 3.26 min), tentatively assigned as: (S)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(380 mg, 20.0% yield);

SFC condition: Column: Chiralpak AD 100×4.6 mm I.D., 3 μm Mobile phase: A: CO₂ B: Methanol (0.05% DEA) Isocratic: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature: 40° C., BPR: 120 bar.

1-benzyl-N-((6S)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (6S)-6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (100 mg, 0.39 mmol), 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (120 mg, 0.59 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (79 mg, 0.59 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (110 mg, 0.59 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonia hydroxide in water) to afford 1-benzyl-N-((6 S)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol o[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide as a white solid (100 mg, 57%):

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.56 (d, J=7.6 Hz, 1H), 7.41-7.28 (m, 5H), 6.29 (d, J=8.8 Hz, 1H), 5.48 (s, 2H), 4.35-4.26 (m, 2H), 4.19-4.07 (m, 1H), 3.22 (d, J=1.6 Hz, 3H), 2.94-2.87 (m, 1H), 2.41-2.32 (m, 2H), 2.00-1.93 (m, 1H), 1.89-1.81 (m, 1H).

LCMS R_(T)=0.99 min; m/z=442.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.99 min, ESI+ found [M+H]=442.2.

Example 284 WX Method NNNNN

1-benzyl-N-((6R)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (6R)-6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (106 mg, 0.41 mmol), 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid (83 mg, 0.41 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (79 mg, 0.59 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (110 mg, 0.59 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.05% ammonia hydroxide) to afford 1-benzyl-N-[(6R)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (105.3 mg, 57%) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 7.40-7.29 (m, 5H), 6.28 (d, J=8.8 Hz, 1H), 5.48 (s, 2H), 4.33-4.29 (m, 2H), 4.17-4.16 (m, 1H), 3.321 (s, 3H), 2.93-2.88 (m, 1H), 2.59-2.50 (m, 1H), 2.37-2.36 (m, 1H), 1.96-1.84 (m, 2H).

LCMS R_(T)=1.77 min; m/z=442.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.77 min, ESI+ found [M+H]=442.2.

Example 285 WX Method LLLLL

5-benzyl-N-((6S)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of (6S)-6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (100 mg, 0.39 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (79 mg, 0.39 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (79 mg, 0.59 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (110 mg, 0.59 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonia hydroxide in water) to afford 5-benzyl-N-((6 S)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol o[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide as a white solid (100 mg, 57%):

¹H NMR (400 MHz, DMSO-d₆) δ 7.34-7.21 (m, 5H), 6.29 (d, J=8.4 Hz, 1H), 4.35-4.26 (m, 2H), 4.20-4.15 (m, 1H), 4.11 (s, 2H), 3.22 (d, J=1.6 Hz, 3H), 2.93-2.88 (m, 1H), 2.59-2.57 (m, 1H), 2.44-2.35 (m, 1H), 2.01-1.93 (m, 1H), 1.90-1.81 (m, 1H). LCMS R_(T) 0.98=min; m/z=442.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.98 min, ESI+ found [M+H]=442.2.

Example 286 WX Method MMMMM

5-benzyl-N-((6R)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of (6R)-6-amino-2-(2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (100 mg, 0.39 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (79 mg, 0.39 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (79 mg, 0.59 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (110 mg, 0.59 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (20-50% acetonitrile in water and 0.05% ammonia hydroxide) to afford 5-benzyl-N-((6R)-2-(2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (101 mg, 58% yield) as white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.32-7.20 (m, 5H), 6.26 (d, J=8.0 Hz, 1H), 4.32-4.27 (m, 2H), 4.15-4.09 (m, 3H), 3.19 (s, 3H), 2.89-2.86 (m, 1H), 2.66-2.63 (m, 1H) 2.56-2.55 (m, 1H), 1.95-1.85 (m, 1H), 1.84-1.82 (m, 1H). LCMS R_(T)=1.74 min; m/z=442.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.74 min, ESI+ found [M+H]=442.2.

Example 287 WX Method NN

1-cyclopropyl-N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

Step 1: (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

(6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.5 g, 7.7 mmol) was separated by chiral SFC (SFCl₃; Chiralpak OD (250 mm*30 mm, 5 um); Supercritical CO₂/MeOH+NH₃*H₂O=20/20; 60 ml/min) to afford:

(6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (Peak 1, R_(T)=2.757 min) (400 mg, 27%) as white solids. (6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (Peak 2, R_(T)=3.846 min) (350 mg, 23%) as white solids.

Step 2: 1-cyclopropyl-N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.10 mmol), 1-cyclopropyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (23 mg, 0.10 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (30 mg, 0.16 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (25% to 55% acetonitrile, 0.05% ammonia hydroxide in water) to give 1-cyclopropyl-N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-methyl-1,3-dihydrofuro[3, 4-c]pyridine-6-carboxamide (13 mg, 30%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 7.92 (s, 1H), 6.10 (s, 1H), 5.13-5.04 (m, 2H), 4.58-4.55 (m, 1H), 4.35-4.22 (m, 2H), 3.33 (s, 3H), 2.92-2.85 (m, 1H), 2.27-2.21 (m, 4H), 1.48 (s, 3H), 1.28-1.23 (m, 1H), 0.47-0.25 (m, 4H). LCMS R_(T)=0.68 min; m/z=396.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.68 min, ESI+ found [M+H]=396.0.

Example 288 WX Method TTT

1-(4-chlorobenzyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL) was added potassiumcarbonate (329 mg, 2.38 mmol) and 1-(bromomethyl)-4-chlorobenzene (244 mg, 1.19 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methyl alcohol in water and 0.05% ammonia hydroxide) to afford 1-(4-chlorobenzyl)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (63.3 mg, 18%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.52 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 6.04 (s, 1H), 5.47 (s, 2H), 4.29-4.21 (m, 2H), 4.19-4.05 (m, 1H), 3.17 (s, 3H), 2.57-2.45 (m, 2H), 1.86-1.80 (m, 1H), 0.84-0.82 (m, 2H), 0.65-0.59 (m, 2H). LCMS R_(T)=1.84 min; m/z=440.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.84 min, ESI+ found [M+H]=440.1.

Example 289 WX Method JJJ

(S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((1-methylcyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 1-(iodomethyl)-1-methylcyclopropane

To a stirred suspension of triphenylphosphine (457 mg, 1.74 mmol) in dichloromethane (10 mL) was added imidazole (118 mg, 1.74 mmol) and iodine (442 mg, 1.74 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, and a solution of 1-methylcyclopropanemethanol (100 mg, 1.16 mmol) in dichloromethane (5 mL) was added. The reaction mixture was allowed to warm to 25° C. and stirred for 2 h and then quenched by addition of brine (10 mL). The mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (2×10 mL), aqueous sodium thiosulfate (5%, 10 mL), dried over sodium sulfate and evaporated under reduced pressure to afford 1-(iodomethyl)-1-methylcyclopropane (200 mg, 88%) as colorless oil, used in the next step without further purification.

Step 2: (S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((1-methylcyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (147 mg, 0.51 mmol) and potassium carbonate (141 mg, 1.02 mmol) in N,N-dimethylformamide (3 mL) was added 1-(iodomethyl)-1-methylcyclopropane (100 mg, 0.51 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC (acetonitrile 0-40%/0.1% ammonia hydroxide in water) to afford (S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((1-methylcyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide (12 mg, 7%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 6.14 (s, 1H), 4.88-4.54 (m, 1H), 4.34-4.32 (m, 1H), 4.27-4.24 (m, 1H), 4.15 (s, 2H), 3.35 (s, 3H), 2.92-2.85 (m, 1H), 2.32-2.26 (m, 4H), 1.05 (s, 3H), 0.76-0.73 (m, 2H), 0.50-0.47 (m, 2H).

LCMS R_(T)=1.36 min, m/z=358.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.36 min, ESI+ found [M+H]⁺=358.2.

Example 290 WX Method JJJJ

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-(4-fluorophenyl)ethyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (328 mg, 2.38 mmol) and 1-(1-bromoethyl)-4-fluorobenzene (193 mg, 0.95 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-(4-fluorophenyl)ethyl)-1H-1,2,4-triazole-3-carboxamide (40.1 mg, 11%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (s, 1H), 8.52 (d, J=7.6 Hz, 1H), 7.40-7.37 (m, 2H), 7.22-7.18 (m, 2H), 6.06 (s, 1H), 5.86-5.81 (m, 1H), 4.32-4.21 (m, 2H), 4.09-4.08 (m, 1H), 3.19 (s, 3H), 2.59-2.55 (m, 1H), 2.40-2.32 (m, 1H), 1.87-1.83 (m, 4H), 0.87-0.84 (m, 2H), 0.67-0.64 (m, 2H). LCMS R_(T)=0.80 min; m/z=438.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=438.2.

Example 291 WX Method KKKK

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((2,2-difluorocyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (328 mg, 2.38 mmol) and 2-(bromomethyl)-1,1-difluoro-cyclopropane (163 mg, 0.95 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (47-77% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((2,2-difluorocyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide (57 mg, 18%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.56 (d, J=8.0 Hz, 1H), 6.07 (s, 1H), 4.45-4.30 (m, 4H), 4.24-4.09 (m, 1H), 3.20 (s, 3H), 2.61-2.58 (m, 1H), 2.34-2.32 (m, 2H), 1.87-1.85 (m, 1H), 1.83-1.80 (m, 1H), 1.77-1.67 (m, 1H), 0.86-0.84 (m, 2H), 0.69-0.64 (m, 2H). LCMS R_(T)=0.74 min; m/z=406.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.74 min, ESI+ found [M+H]=406.1.

Example 292 WX Method LLLL

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (328 mg, 2.38 mmol) and (1-bromoethyl)benzene (176 mg, 0.95 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide (34 mg, 10%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.54 (d, J=7.6 Hz, 1H), 7.36-7.32 (m, 5H), 6.06 (s, 1H), 5.82-5.80 (m, 1H), 4.32-4.21 (m, 2H), 4.12-4.08 (m, 1H), 3.19 (s, 3H), 2.57-2.50 (m, 1H), 2.37-2.33 (m, 1H), 1.86-1.84 (m, 4H), 0.86-0.84 (m, 2H), 0.67-0.65 (m, 2H).

LCMS R_(T)=0.79 min; m/z=420.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=420.1.

Example 293 WX Method BBBBBBB

5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (20 mg, 0.10 mmol), 3-amino-1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (15 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% NH₄HCO₃ in water) to give 5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (8.4 mg, 27% yield) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.66 (s, 1H), 7.31-7.24 (m, 5H), 7.01 (s, 1H), 4.45-4.41 (m, 2H), 4.16 (s, 2H), 4.04-3.96 (m, 1H), 3.35 (s, 3H), 2.80-2.72 (m, 1H), 2.21-2.13 (m, 1H). LCMS R_(T)=1.118 min; m/z=366.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 1.118 min, ESI+ found [M+H]=366.1.

Example 294 WX Method ZZZZZZ

(1R)-1-ethyl-1-methyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[,15-a][1,3]diazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (21 mg, 0.10 mmol), 3-amino-1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (15 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% NH₄HCO₃ in water) to give (1R)-1-ethyl-1-methyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (9.8 mg, 32%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.01 (s, 1H), 5.16-5.15 (m, 2H), 4.65-4.60 (m, 1H), 4.66-4.41 (m, 1H), 4.05-3.98 (m, 1H), 3.37 (s, 3H), 2.84-2.80 (m, 1H), 2.21-2.17 (m, 1H), 1.88-1.82 (m, 2H), 1.46 (s, 3H), 0.77 (t, J=7.2 Hz, 3H). LCMS R_(T)=1.385 min; m/z=370.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 1.385 min, ESI+ found [M+H]=370.2.

Example 295 WX Method AAAAAA

1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-benzyltriazole-4-carboxylic acid (20 mg, 0.10 mmol), 3-amino-1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (15 mg, 0.08 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% NH₄HCO₃ in water) to give 1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,3-triazole-4-carboxamide (12.1 mg, 39%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 7.61 (s, 1H), 7.36-7.32 (m, 5H), 6.98 (s, 1H), 5.63 (s, 2H), 4.61-4.56 (m, 1H), 4.44-4.38 (m, 1H), 4.03-3.98 (m, 1H), 3.34 (s, 3H), 2.75-2.69 (m, 1H), 2.24-2.18 (m, 1H).

LCMS R_(T)=1.329 min; m/z=366.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 1.329 min, ESI+ found [M+H]=366.2.

Example 296 WX Method MM

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

Step 1: Methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate

To a solution of methyl 5-bromo-1h-pyrazolo[3,4-b]pyridine-3-carboxylate (1.0 g, 3.91 mmol) in tetrahydrofuran (20 mL) was added triethylamine (790 mg, 7.81 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (977 mg, 5.86 mmol). The mixture was stirred at 25° C. for 4 h and then diluted with water (10 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 6% ethyl acetate in petroleum ether) to afford methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate (560 mg, 37%) as colorless oil, used as is in the next step.

Step 2: Methyl 5-[1-(trifluoromethyl)vinyl]-1-(2-trimethylsilylethoxymethyl) pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate (560 mg, 1.45 mmol), 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (482 mg, 2.17 mmol), 1,1′-bis (diphenylphosphino)ferrocene palladium dichloride (106. mg, 0.14 mmol) and cesium carbonate (944 mg, 2.9 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 110° C. for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to afford methyl 5-[1-(trifluoromethyl)vinyl]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate (450 mg, 77%) as a white solid: LCMS R_(T)=0.999 min; m/z=402.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.999 min, ESI+ found [M+H]=402.1.

Step 3: Methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl 5-[1-(trifluoromethyl)vinyl]-1-(2-trimethyl silyl ethoxymethyl) pyrazolo[3,4-b]pyridine-3-carboxylate (150 mg, 0.37 mmol) and 10% palladium on carbon (40 mg, 0.04 mmol) in methanol (5 mL) was hydrogenated (50 psi) at 25° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure affording crude methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethyl silylethoxymethyl) pyrazolo[3,4-b]pyridine-3-carboxylate (111 mg, 74%) as a white solid: LCMS R_(T)=0.998 min; m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.998 min, ESI+ found [M+H]=404.1

Step 4: 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylic acid

A mixture of methyl 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilyl ethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylate (111 mg, 0.28 mmol) and lithium hydroxide hydrate (33 mg, 1.38 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 29° C. for 18 h. The organic solvent was evaporated under reduced pressure and the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The solid was removed by filtration and the aqueous layer was concentrated under reduced pressure affording crude 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethyl silylethoxymethyl)pyrazolo[3,4-b]pyridine-3-carboxylic acid (68 mg, 63%) as a white solid: LCMS R_(T)=2.077 min; m/z=390.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.04% formic acid over 3 mins) retention time 2.077 min, ESI+ found [M+H]=390.1

Step 5: 5-(2,2,2-trifluoro-1-methyl-ethyl)-1h-pyrazolo[3,4-b]pyridine-3-carboxylic acid

To a solution of 5-(2,2,2-trifluoro-1-methyl-ethyl)-1-(2-trimethylsilylethoxymethyl) pyrazolo[3,4-b]pyridine-3-carboxylic acid (68 mg, 0.17 mmol) in water (5 mL) was added hydrochloric acid (4.0 M in dioxane, 0.2 mL, 0.80 mmol). The reaction mixture was stirred at ° C. for 18 h and then concentrated under reduced pressure affording 5-(2,2,2-trifluoro-1-methyl-ethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (32 mg, 70%) as a white solid: LCMS R_(T)=0.716 min; m/z=259.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.716 min, ESI+ found [M+H]=259.9.

Step 6: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A mixture of 5-(2,2,2-trifluoro-1-methyl-ethyl)-1h-pyrazolo[3,4-b]pyridine-3-carboxylic acid (32 mg, 0.12 mmol), (3s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (26 mg, 0.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (20 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (28 mg, 0.15 mmol) in N, N-dimethylformamide (5 mL) was stirred at 25° C. for 3 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 41-51%/0.05% ammonia in water) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (24 mg 45%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 14.35 (br. s, 1H), 8.72-8.57 (m, 2H), 8.44 (s, 1H), 7.56-7.47 (m, 1H), 7.40-7.19 (m, 3H), 4.98-4.89 (m, 1H), 4.71-4.63 (m, 1H), 4.50-4.43 (m, 1H), 4.17-4.06 (m, 1H), 3.34 (m, 3H), 1.51 (d, J=7.2 Hz, 3H). LCMS R_(T)=0.850 min; m/z=434.4 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.850 min, ESI+ found [M+H]=434.4.

Example 297 WX Method CCCCCCC

(S)-1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (20 mg, 0.055 mmol) was separated by chiral SFC (Column: Chiralpak AS-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.) to afford (S)-1-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. (R_(T)=4.174 min, 8.3 mg, 41%) as white solid. LCMS R_(T)=1.664 min; m/z=366.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 1.664 min, ESI+ found [M+H]=366.1.

Example 298 WX Method FFFF

(R)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (6R)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (26 mg, 0.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (26-56% acetonitrile in water and 0.05% ammonia hydroxide) to afford (R)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (9.2 mg, 22%) as a white solid:

¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.46-7.44 (m, 1H), 7.04-6.97 (m, 2H), 5.99 (s, 1H), 5.51 (s, 2H), 4.52-4.47 (m, 1H), 4.28-4.26 (m, 1H), 4.22-4.17 (m, 1H), 3.29 (s, 3H), 2.83-2.78 (m, 1H), 2.23-2.20 (m, 1H), 1.91-1.86 (m, 1H), 0.93-0.91 (m, 2H), 0.72-0.70 (m, 2H). LCMS R_(T)=0.79 min; m/z=442.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=442.1.

Example 299 WX Method EE

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2′,3′,5′,6′-tetrahydro-3H-spiro[furo[3,4-c]pyridine-1,4′-pyran]-6-carboxamide

Step 1: 6-chlorospiro[furo[3,4-c]pyridine-1,4′-tetrahydropyran]-3-one

To a stirred solution of 2,2,6,6-tetramethylpiperidine (2.7 g, 19.0 mmol) in tetrahydrofuran (30 mL) was added n-butyllithium (2.5 M, 10 mL, 25.0 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 40 min and then 6-chloronicotinic acid (1.0 g, 6.4 mmol) in tetrahydrofuran (10 mL) was added. The resulting mixture was stirred at −78° C. for another 2 h, and then tetrahydro-4h-pyran-4-one (1.3 g, 12.7 mmol) was added dropwise. After addition, the reaction was warmed up to 25° C. and stirred for 16 h before quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to afford 6-chlorospiro[furo[3,4-c]pyridine-1,4′-tetrahydropyran]-3-one (900 mg, 59%) as yellow oil: ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.16 (s, 1H), 4.01-3.86 (m, 2H), 3.67-3.64 (m, 2H), 2.31-2.25 (m, 2H), 1.79-1.61 (m, 2H).

Step 2: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-3-ol

To a solution of 6-chlorospiro[furo[3,4-c]pyridine-1,4′-tetrahydropyran]-3-one (900 mg, 3.76 mmol) in dichloromethane (40 mL) was added diisobutylaluminum hydride (1.0 M, 9.0 mL, 9.0 mmol) dropwise at −70° C. After addition, stirring at −70° C. was continued for 2 h and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-3-ol (790 mg, 87%) as yellow oil:

LCMS R_(T)=0.49 min; m/z=241.9 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.49/min, ESI+ found [M+H]=241.9.

Step 3: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]

To a solution of 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-3-ol (400. mg, 1.66 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (944 mg, 8.28 mmol) dropwise at 0° C. The reaction was stirred for 30 min at 0° C., and triethyl silane (577 mg, 4.97 mmol) was added. After addition, the mixture was allowed to warm to 25° C. over 3 h and then quenched by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran] (340 mg, 91%) as yellow oil: LCMS R_(T)=0.93 min; m/z=226.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.93/min, ESI+ found [M+H]=226.1.

Step 4: methyl spiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-6-carboxylate

A solution of 6-chlorospiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran] (340 mg, 1.41 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (103 mg, 0.14 mmol) and triethylamine (1.4 g, 14.1 mmol) in methanol (20 mL) was heated at 80° C. for 12 h under carbon oxide (25 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl spiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-6-carboxylate (160 mg, 46%) as a yellow solid: LCMS R_(T)=0.55 min; m/z=249.8 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.55/min, ESI+ found [M+H]=249.8.

Step 5: spiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-6-carboxylic acid

A mixture of methyl spiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-6-carboxylate (30 mg, 0.12 mmol) and lithium hydroxide hydrate (14 mg, 0.60 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25° C. for 2 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH=4 by addition of hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure to afford crude spiro[3H-furo[3,4-c]pyri dine-1,4′-tetrahydropyran]-6-carboxylic acid (25 mg, 88%) as a white solid: LCMS R_(T)=1.07 min; m/z=236.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% trifluoacetic acid over 3 mins) retention time 1.07/min, ESI+ found [M+H]=236.1.

Step 6: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2′,3′,5′,6′-tetrahydro-3H-spiro[furo[3,4-c]pyridine-1,4′-pyran]-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (20 mg, 0.11 mmol), spiro[3H-furo[3,4-c]pyridine-1,4′-tetrahydropyran]-6-carboxylic acid (25 mg, 0.11 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.13 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 27-57/0.05% ammonia hydroxide in water) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2′,3′,5′,6′-tetrahydro-3H-spiro[furo[3,4-c]pyridine-1,4′-pyran]-6-carboxamide (19 mg, 44%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.93 (s, 1H), 7.44-7.43 (m, 1H), 7.34-7.31 (m, 2H), 7.26-7.25 (m, 1H), 5.20 (s, 2H), 5.05-5.02 (m, 1H), 4.67-4.64 (m, 1H), 4.43-4.40 (m, 1H), 3.92-3.41 (m, 4H), 3.31 (s, 3H), 2.09-2.01 (m, 2H), 1.68-1.65 (m, 2H). LCMS R_(T)=2.20 min; m/z=410.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 2.20/min, ESI+ found [M+H]=410.1.

Example 300 WX Method EEEEE

(S)-5-benzyl-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (20 mg, 0.10 mmol) (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium bicarbonate in water) to give (S)-5-benzyl-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (12.2 mg, 37%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.31-7.23 (m, 5H), 4.44-4.39 (m, 1H), 4.22-4.18 (m, 2H), 4.15 (s, 2H), 3.30 (s, 3H), 2.81-2.72 (m, 1H), 2.18-2.16 (m, 4H), 2.00 (s, 3H). LCMS R_(T)=0.74 min; m/z=394.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.74 min, ESI+ found [M+H]=394.1.

Example 301 WX Method MMM

(S)-1-(2,6-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.21 mmol) and potassium carbonate (86 mg, 0.62 mmol) in N,N-dimethylformamide (5 mL) was added 2-(bromomethyl)-1,3-difluoro-benzene (52 mg, 0.25 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC (methanol 45-75%/0.05% ammonia hydroxide in water) to afford (S)-1-(2,6-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (23.8 mg, 27%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.45-7.42 (m, 1H), 7.05-7.01 (m, 2H), 6.08 (s, 1H), 5.57 (s, 2H), 4.48-4.46 (m, 1H), 4.27-4.25 (m, 1H), 4.24-4.19 (m, 1H), 3.29 (s, 3H), 2.83-2.77 (m, 1H), 2.25-2.21 (m, 4H).

LCMS R_(T)=0.739 min, m/z=416.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.739 min, ESI+ found [M+H]=416.1.

Example 302 WX Method MMMM

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,6-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2-(bromomethyl)-1,3-difluoro-benzene (47 mg, 0.23 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (52-82% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,6-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (29 mg, 35%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.49-7.42 (m, 1H), 7.08-7.02 (m, 2H), 5.99 (s, 1H), 5.59 (s, 2H), 4.52-4.47 (m, 1H), 4.28-4.24 (m, 1H), 4.22-4.18 (m, 1H), 3.31 (s, 3H), 2.85-2.78 (m, 1H), 2.24-2.22 (m, 1H), 1.91-1.88 (m, 1H), 0.94-0.91 (m, 2H), 0.74-0.72 (m, 2H). LCMS R_(T)=0.78 min; m/z=422.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=442.2

Example 303 WX Method NNNN

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (66 mg, 0.48 mmol) and 3,5-difluorobenzylbromide (47 mg, 0.23 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(3,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (18.4 mg, 22%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 6.97-6.91 (m, 3H), 5.99 (s, 1H), 5.49 (s, 2H), 4.54-4.50 (m, 1H), 4.28-4.26 (m, 1H), 4.21-4.14 (m, 1H), 3.30 (s, 3H), 2.86-2.80 (m, 1H), 2.29-2.24 (m, 1H), 1.91-1.87 (m, 1H), 0.94-0.91 (m, 2H), 0.74-0.71 (m, 2H). LCMS R_(T)=0.80 min; m/z=442.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=442.1.

Example 304 WX Method OOOO

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2,5-difluorobenzyl bromide (47 mg, 0.23 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (53-83% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (15.5 mg, 18%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 7.31-7.25 (m, 3H), 6.06 (s, 1H), 5.54 (s, 2H), 4.30-4.26 (m, 2H), 4.25-4.21 (m, 1H), 3.19 (s, 3H), 2.54-2.52 (m, 1H), 2.50-2.33 (m, 1H), 1.85-1.83 (m, 1H), 0.86-0.84 (m, 2H), 0.68-0.64 (m, 2H). LCMS R_(T)=0.78 min; m/z=442.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=442.1.

Example 305 WX Method LLL

(S)-1-(2,5-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (86 mg, 0.62 mmol) and 2,5-difluorobenzyl bromide (52 mg, 0.25 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC (methanol 50-80%/0.05% ammonia hydroxide in water) to afford (S)-1-(2, 5-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (28.4 mg, 32%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.18-7.11 (m, 3H), 6.09 (s, 1H), 5.53 (s, 2H), 4.53-4.48 (m, 1H), 4.30-4.27 (m, 1H), 4.25-4.19 (m, 1H), 3.30 (s, 3H), 2.84-2.78 (m, 1H), 2.28-2.22 (m, 4H). LCMS R_(T)=0.751 min, m/z=416.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.751 min, ESI+ found [M+H]=416.1.

Example 306 WX Method PPPP

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,3-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2,3-dichlorobenzyl bromide (55 mg, 0.23 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (55-85% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,3-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide (13.6 mg, 15%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.42-7.38 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.06 (s, 1H), 5.64 (s, 2H), 4.31-4.23 (m, 2H), 4.21-4.07 (m, 1H), 3.19 (s, 3H), 2.58-2.50 (m, 1H), 2.44-2.32 (m, 1H), 1.85-1.83 (m, 1H), 0.86-0.84 (m, 2H), 0.68-0.64 (m, 2H). LCMS R_(T)=0.83 min; m/z=474.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.83 min, ESI+ found [M+H]=474.1.

Example 307 WX Method QQQQ

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (79 mg, 0.57 mmol) and 2,4-dichlorobenzyl bromide (55 mg, 0.23 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (60-90% methanol in water and 0.05% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,4-dichlorobenzyl)-1H-1,2,4-tri azole-3-carboxamide (16.7 mg, 18%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.41-7.30 (m, 2H), 5.99 (s, 1H), 5.57 (s, 2H), 4.53-4.48 (m, 1H), 4.28-4.26 (m, 1H), 4.20-4.17 (m, 1H), 3.29 (s, 3H), 2.85-2.78 (m, 1H), 2.27-2.22 (m, 1H), 1.91-1.86 (m, 1H), 0.93-0.91 (m, 2H), 0.77-0.71 (m, 2H). LCMS R_(T)=0.83 min; m/z=474.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.83 min, ESI+ found [M+H]=474.1.

Example 308 WX Method IIII

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((1-methylcyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide and (R)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (3.6 g, 16.3 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (4.4 g, 24.5 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (220 mg, 1.63 mmol) and 1H-1,2,4-triazole-3-carboxylic acid (2.2 g, 19.6 mmol) in N,N-dimethylformamide (60 mL) was stirred at 25° C. for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-3% methanol in dichloromethane) to afford N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (2.6 g, 46%) as white solid: LCMS R_(T)=1.068 min; m/z=316.1 (M+H)⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium bicarbonate over 3.0 mins) retention time 1.068 min, ESI+ found [M+H]=316.1.

2.4 g of this material was separated by chiral SFC to afford:

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (peak 1, retention time: 3.657 min) (700 mg, 28%). (R)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (peak 2, retention time: 4.150 min) (900 mg, 36%).

SFC condition: Column: Chiralcel OD-3 50×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:methanol (0.05% DEA) Gradient: hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min Flow rate: 4 mL/min Column temp: 40° C.

Step 2: (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((1-methylcyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a solution of (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (126 mg, 0.40 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (88 mg, 0.63 mmol) and 1-(iodomethyl)-1-methyl-cyclopropane (93 mg, 0.48 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by RP-HPLC (0 to 40% acetonitrile in water and 0.1% ammonia hydroxide) to afford (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((1-methylcyclopropyl)methyl)-1H-1,2,4-triazole-3-carboxamide (30 mg, 20%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H), 6.00 (s, 1H), 4.55-4.51 (m, 1H), 4.30-4.24 (m, 1H), 4.22-4.19 (m, 1H), 4.12 (s, 2H), 3.30 (s, 3H), 2.89-2.83 (m, 1H), 2.27-2.24 (m, 1H), 1.92-1.87 (m, 1H), 1.03 (s, 3H), 0.94-0.91 (m, 2H), 0.75-0.71 (m, 4H), 0.47-0.44 (m, 2H). LCMS R_(T)=0.96 min; m/z=384.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 2 mins) retention time 0.96 min, ESI+ found [M+H]=384.3.

Example 309 WX Method N

7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide

Step 1: 2-chloro-7-methyl-7-propylfuro[3,4-d]pyrimidin-5(7H)-one

To a stirred solution of 2,2,6,6-tetramethylpiperidine (13.4 g, 94.6 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M, 50.5 mL, 126.2 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 40 min and then 2-chloropyrimidine-5-carboxylic acid (5.0 g, 31.5 mmol) in tetrahydrofuran (20 mL) was added. The resulting mixture was stirred at −78° C. for another 2 h, and then 2-pentanone (5.4 g, 63.1 mmol) was added dropwise. After addition, the reaction was warmed up to 25° C. and stirred for 16 h before quenched by addition of saturated aqueous ammonium chloride. The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) affording 2-chloro-7-methyl-7-propylfuro[3, 4-d]pyrimidin-5(7H)-one (1.9 g, 26%) as yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 2.06-2.04 (m, 1H), 2.00-1.96 (m, 1H), 1.68 (s, 3H), 1.39-1.36 (m, 1H), 0.99-0.95 (m, 1H), 0.90-0.86 (m, 3H).

Step 2: 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

To a stirred solution of 2-chloro-7-methyl-7-propylfuro[3,4-d]pyrimidin-5(7H)-one (1.9 g, 8.3 mmol) in toluene (30 mL) was added diisobutylaluminumhydride (1.0 M, 20.8 mL, 20.8 mmol) dropwise at −78° C. After addition, the mixture was stirred at −78° C. for 1 h and then quenched by addition of saturated aqueous ammonium chloride (10 mL) and saturated aqueous sodium potassium tartrate (30 mL). Stirring was continued for 2 h at 25° C. and the mixture was then extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) affording 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (820 mg, 43%) as light yellow oil: LCMS R_(T)=0.640 min; m/z=228.7 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.640 min, ESI+ found [M+H]⁺=228.7.

Step 3: 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine

To a stirred solution of 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (820 mg, 3.6 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1.33 mL, 17.9 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then triethylsilane (2.86 mL, 17.9 mmol) was added dropwise at 0° C. After addition, the mixture was warmed up to 25° C. and stirred for 15 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) affording 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine (700 mg, 92%) as light yellow oil.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.707 min, ESI+ found [M+H]⁺=212.8.

Step 4: 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile

To a stirred solution of 2-chloro-7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine (700 mg, 3.3 mmol) in dimethyl sulfoxide (5 mL) was added a solution of sodium cyanide (322 mg, 6.6 mmol) in water (5 mL) and 1,4-diazabicyclo[2.2.2]octane (74 mg, 0.66 mmol). The mixture was stirred at 25° C. for 15 h and then poured into water (10 mL). The resulting solution was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) affording 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile (200 mg, 30%) as light yellow oil: LCMS R_(T)=0.708 min; m/z=203.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.708 min, ESI+ found [M+H]⁺=203.8.

Step 5: methyl 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate

To a stirred solution of 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile (200 mg, 0.98 mmol) in methanol (4 mL) was added hydrochloric acid (4.0 M in MeOH, 2.5 mL, 10 mmol) at 0° C. The resulting mixture was warmed up to 25° C. and stirred for 15 h. The mixture was concentrated under reduced pressure affording crude methyl 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (120 mg, 52%) as white solids: LCMS R_(T)=0.656 min; m/z=236.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.656 min, ESI+ found [M+H]⁺=236.9.

Step 6: 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid

A mixture of methyl 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (120 mg, 0.51 mmol) and lithium hydroxide (121 mg, 5.1 mmol) in tetrahydrofuran (12 mL) and water (6 mL) was stirred for 20 h at 25° C. The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M) and then extracted with ethyl acetate (3×45 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure affording crude 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (100 mg, 88%) as light yellow oil, used in the next step without further purification.

Step 7: 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide

A mixture of 7-methyl-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (48 mg, 0.22 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (35 mg, 0.18 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (42 mg, 0.22 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (29 mg, 0.22 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 1 h. The solvent was evaporated under reduced pressure and the residue purified it by RP-HPLC (acetonitrile 36-66%/0.05% ammonium hydroxide in water) affording 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-propyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide (33.5 mg, 46%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 7.46-7.44 (m, 1H), 7.36-7.24 (m, 3H), 5.20-5.12 (m, 2H), 5.08-5.03 (m, 1H), 4.71-4.66 (m, 1H), 4.48-4.42 (m, 1H), 3.44 (s, 3H), 1.96-1.79 (m, 2H), 1.54-1.38 (m, 4H), 1.08-0.95 (m, 1H), 0.89-0.85 (m, 3H). LCMS R_(T)=1.056 min; m/z=397.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.056 min, ESI+ found [M+H]⁺=397.2.

Example 310 WX Method AA

7-ethyl-7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5, 7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide

Step 1: 2-chloro-7-ethyl-7-methylfuro[3,4-d]pyrimidin-5(7H)-one

To a stirred solution of 2,2,6,6-tetramethylpiperidine (13.5 g, 95.6 mmol) in tetrahydrofuran (300 mL) was added n-butyllithium (2.5 M, 50 mL, 125.0 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 40 min and then 2-chloropyrimidine-5-carboxylic acid (5.0 g, 31.5 mmol) in tetrahydrofuran (20 mL) was added. The resulting mixture was stirred at −78° C. for another 2 h, and then butan-2-one (6.8 g, 94.6 mmol) was added dropwise. After addition, the reaction was warmed up to 25° C. and stirred for 16 h before quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×80 mL). The combined organic layer was washed water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 2-chloro-7-ethyl-7-methylfuro[3,4-d]pyrimidin-5(7H)-one (1.0 g, 15%) as yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, 1H), 2.15-2.03 (m, 2H), 1.69 (s, 3H), 0.81 (t, J=7.2 Hz, 3H).

Step 2: 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

To a solution of 2-chloro-7-ethyl-7-methylfuro[3,4-d]pyrimidin-5(7H)-one (1.0 g, 4.7 mmol) in toluene (30 mL) was added diisobutylaluminum hydride (1.0 M, 9.4 mL, 9.4 mmol) dropwise at −70° C. After addition, stirring at −70° C. was continued for 2 h and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The resulting mixture was filtered and the filtrate was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (0.70 g, 70%) as yellow oil used as is in the next step.

Step 3: 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine

To a solution of 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (700 mg, 3.3 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1.86 g, 63.5 mmol) dropwise at 0° C. The reaction was stirred for 30 min at 0° C., and triethyl silane (1.9 g, 16.5 mmol) was added. After addition, the mixture was allowed to warm to 25° C. over 3 h and then quenched by addition of saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to afford 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (450 mg, 69%) as yellow oil.

Step 4: 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile

To a stirred solution of 2-chloro-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (450 mg, 2.27 mmol) in dimethyl sulfoxide (5 mL) and water (2 mL) was added sodium cyanide (222 mg, 4.54 mmol) and 1,4-diazabicyclo[2.2.2]octane (74 mg, 0.66 mmol). The mixture was stirred at 25° C. for 16 h and then poured into water (10 mL). The resulting solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile (140 mg, 33%) as yellow oil, used as is in the next step.

Step 5: methyl 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate

To a solution of 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carbonitrile (140 mg, 0.74 mmol) in methanol (4 mL) was added hydrochloric acid (4.0 M in MeOH, 2.0 mL, 8 mmol) at 0° C. The resulting mixture was warmed up to RT and stirred for 16 h. Then the mixture was concentrated under reduced pressure to afford crude methyl 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (120 mg, 73%) as a white solid, used in the next step without any further purification.

Step 6: 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid

A mixture of methyl 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate (120 mg, 0.54 mmol) and lithium hydroxide hydrate (113 mg, 2.70 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25° C. for 2 h. After evaporation of the organic solvent under reduced pressure, the aqueous residue was adjusted to pH=5 by addition of hydrochloric acid (1.0 M). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 1-methyl-1-(2,2,2-trifluoroethyl)-1,3-dihydrofuro [3,4-c]pyridine-6-carboxylic acid (90 mg, 80%) as a yellow solid, used in the next step without further purification.

Step 7: 7-ethyl-7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide

A mixture of 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (20 mg, 0.10 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (20 mg, 0.10 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.11 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (15 mg, 0.11 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 31-61%/0.05% NH₄OH in water) to afford 7-ethyl-7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide (24.20 mg, 65%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 1H), 7.46-7.43 (m, 1H), 7.34-7.32 (m, 2H), 7.27-7.24 (m, 1H), 5.19-5.15 (m, 2H), 5.08-5.03 (m, 1H), 4.71-4.66 (m, 1H), 4.47-4.44 (m, 1H), 3.44 (s, 3H), 2.01-1.85 (m, 2H), 1.49 (s, 3H), 0.80 (t, J=7.2 Hz, 3H). LCMS R_(T)=0.793 min; m/z=383.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.793 min, ESI+ found [M+H]=383.1.

Example 311 WX Method YYYYY

1-(2,3-difluorobenzyl)-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (60 mg, 0.23 mmol), (1-[(2,3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (84 mg, 0.35 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (47 mg, 0.35 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) to afford 1-(2,3-difluorobenzyl)-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (11.9 mg, 11%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 7.29-7.25 (m, 1H), 7.17-7.12 (m, 2H), 6.20 (s, 1H), 5.58 (s, 2H), 4.53-4.48 (m, 1H), 4.36-4.23 (m, 2H), 3.31 (s, 3H), 2.84-2.79 (m, 2H), 2.26-2.21 (m, 1H), 1.87-1.80 (m, 2H). LCMS R_(T)=0.81 min; m/z=478.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.81 min, ESI+ found [M+H]=478.2.

Example 312 WX Method SSSSS

1-(2,3-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (R)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-[(2,3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (42 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.05% ammonia hydroxide) to afford 1-(2,3-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (38.8 mg, 69%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 7.32-7.27 (m, 1H), 7.19-7.16 (m, 2H), 6.21 (s, 1H), 5.60 (s, 2H), 4.55-4.50 (m, 1H), 4.36-4.34 (m, 1H), 4.27-4.24 (m, 1H), 3.33 (s, 3H), 2.88-2.80 (m, 2H), 2.28-2.26 (m, 1H), 1.90-1.78 (m, 2H). LCMS R_(T)=0.80 min; m/z=478.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=478.1.

Example 313 WX Method ZZZZZ

1-(3,4-difluorobenzyl)-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (60 mg, 0.23 mmol), 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (84 mg, 0.35 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (47 mg, 0.35 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 32-62%/0.05% ammonia hydroxide in water) to afford 1-(3,4-difluorobenzyl)-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (18 mg, 16%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 6.20 (s, 1H), 5.45 (s, 2H), 4.55-4.50 (m, 1H), 4.36-4.34 (m, 1H), 4.26-4.23 (m, 1H), 3.30 (s, 3H), 2.85-2.80 (m, 2H), 2.27-2.26 (m, 1H), 1.89-1.77 (m, 2H). LCMS R_(T)=0.81 min; m/z=478.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.81 min, ESI+ found [M+H]=478.1.

Example 314 WX Method TTTTTT

1-(3,4-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (R)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-[(3,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (42 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (31-61% acetonitrile in water and 0.05% ammonia hydroxide) to afford 1-(3,4-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (37.1 mg, 66%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.35-7.26 (m, 2H), 7.20-7.19 (m, 1H), 6.21 (s, 1H), 5.46 (s, 2H), 4.55-4.50 (m, 1H), 4.37-4.35 (m, 1H), 4.27-4.24 (m, 1H), 3.33 (s, 3H), 2.88-2.80 (m, 2H), 2.28-2.27 (m, 1H), 1.90-1.78 (m, 2H). LCMS R_(T)=0.81 min; m/z=478.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.81 min, ESI+ found [M+H]=478.1.

Example 315 WX Method AAAAAA

1-(2,4-difluorobenzyl)-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (60 mg, 0.23 mmol), 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (84 mg, 0.35 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (47 mg, 0.35 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) to afford 1-(2,4-difluorobenzyl)-N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (28.8 mg, 25%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.44 (s, 1H), 7.01-7.00 (m, 2H), 6.20 (s, 1H), 5.51 (s, 2H), 4.52-4.50 (m, 1H), 4.35-4.22 (m, 2H), 3.31 (s, 3H), 2.82-2.80 (m, 2H), 2.26-2.23 (m, 1H), 1.87-1.80 (m, 2H). LCMS R_(T)=0.80 min; m/z=478.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=478.1.

Example 316 WX Method UUUUU

1-(2,4-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (R)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (42 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (25-55% acetonitrile in water and 0.05% ammonia hydroxide) to afford 1-(2,4-difluorobenzyl)-N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (24.2 mg, 43%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.49-7.43 (m, 1H), 7.06-6.98 (m, 2H), 6.21 (s, 1H), 5.53 (s, 2H), 4.54-4.49 (m, 1H), 4.38-4.34 (m, 1H), 4.27-4.24 (m, 1H), 3.33 (s, 3H), 2.87-2.77 (m, 2H), 2.27-2.26 (m, 1H), 1.90-1.78 (m, 2H). LCMS R_(T)=0.80 min; m/z=478.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=478.2.

Example 317 WX Method BBBBBB

N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (60 mg, 0.23 mmol), 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (78 mg, 0.35 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (47 mg, 0.35 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) to afford N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide(18.3 mg, 17%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.41-7.37 (m, 2H), 7.11-7.07 (m, 2H), 6.20 (s, 1H), 5.45 (s, 2H), 4.54-4.49 (m, 1H), 4.35-4.33 (m, 1H), 4.26-4.23 (m, 1H), 3.30 (s, 3H), 2.84-2.78 (m, 2H), 2.27-2.25 (m, 1H), 1.89-1.78 (m, 2H). LCMS R_(T)=0.80 min; m/z=460.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=460.1.

Example 318 WX Method VVVVV

N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (R)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (39 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (31-61% acetonitrile in water and 0.05% ammonia hydroxide) to afford N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (17.1 mg, 31.5% yield) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.42-7.39 (m, 2H), 7.11 (t, J=8.4 Hz, 2H), 6.21 (s, 1H), 5.46 (s, 2H), 4.55-4.51 (m, 1H), 4.37-4.35 (m, 1H), 4.27-4.24 (m, 1H), 3.33 (s, 3H), 2.88-2.80 (m, 2H), 2.28-2.27 (m, 1H), 1.97-1.80 (m, 2H). LCMS R_(T)=0.79 min; m/z=460.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=460.1.

Example 319 WX Method CCCCCC

(S)—N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (S)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (60 mg, 0.23 mmol), (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carb oxylic acid (58 mg, 0.28 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (47 mg, 0.35 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (63 mg, 0.35 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% ammonia hydroxide in water) to afford (S)—N—((S)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (25 mg, 24%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.86 (s, 1H), 6.21 (s, 1H), 5.19-5.15 (m, 2H), 4.55-4.39 (m, 1H), 4.38-4.35 (m, 1H), 4.30-4.26 (m, 1H), 3.30 (s, 3H), 2.92-2.81 (m, 2H), 2.26-2.25 (m, 1H), 1.94-1.78 (m, 4H), 1.45 (s, 3H), 0.78-0.74 (m, 3H). LCMS R_(T)=0.83 min; m/z=446.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.83 min, ESI+ found [M+H]=446.1.

Example 320 WX Method PPPPP

1-(2,3-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) to afford 1-(2,3-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide as a white solid (13.7 mg, 24%): ¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 7.33-7.24 (m, 1H), 7.22-7.13 (m, 2H), 6.19 (s, 1H), 5.60 (s, 2H), 4.54-4.49 (m, 1H), 4.42-4.33 (m, 1H), 4.30-4.19 (m, 1H), 3.33 (s, 3H), 2.90-2.75 (m, 2H), 2.28-2.24 (m, 1H), 1.94-1.85 (m, 1H), 1.82-1.74 (m, 1H). LCMS R_(T)=1.00 min; m/z=478.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.00 min, ESI+ found [M+H]=478.2.

Example 321 WX Method OOOOO

1-(3,4-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (39 mg, 0.29 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) to afford 1-(3,4-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (16.1 mg, 28%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.36-7.23 (m, 2H), 7.21-7.19 (m, 1H), 6.20 (s, 1H), 5.46 (s, 2H), 4.54-4.49 (m, 1H), 4.42-4.34 (m, 1H), 4.30-4.20 (m, 1H), 3.33 (s, 3H), 2.91-2.75 (m, 2H), 2.31-2.22 (m, 1H), 1.92-1.88 (m, 1H), 1.83-1.74 (m, 1H).

LCMS R_(T)=1.01 min; m/z=478.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.01 min, ESI+ found [M+H]=478.2.

Example 322 WX Method QQQQQ

1-(2,4-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) to afford 1-(2,4-difluorobenzyl)-N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide as a white solid (28.4 mg, 50%): ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.50-7.42 (m, 1H), 7.06-6.96 (m, 2H), 6.19 (s, 1H), 5.52 (s, 2H), 4.53-4.48 (m, 1H), 4.41-4.33 (m, 1H), 4.28-4.17 (m, 1H), 3.33 (s, 3H), 2.90-2.76 (m, 2H), 2.30-2.19 (m, 1H), 1.95-1.84 (m, 1H), 1.83-1.73 (m, 1H). LCMS R_(T)=1.00 min; m/z=478.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.00 min, ESI+ found [M+H]=478.2.

Example 323 WX Method RRRRR

N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1, 5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of (S)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (39 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) to afford N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide as a white solid (23.4 mg, 43%): ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.40 (dd, J=6.0, 8.4 Hz, 2H), 7.10 (t, J=8.8 Hz, 2H), 6.19 (s, 1H), 5.46 (s, 2H), 4.53-4.45 (m, 1H), 4.41-4.34 (m, 1H), 4.30-4.20 (m, 1H), 3.33 (s, 3H), 2.90-2.75 (m, 2H), 2.29-2.14 (m, 1H), 1.95-1.85 (m, 1H), 1.83-1.73 (m, 1H). LCMS R_(T)=0.99 min; m/z=460.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.99 min, ESI+ found [M+H]=460.2.

Example 324 WX Method WWWWW

(R)—N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (R)-6-amino-2-((R)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (24 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (42-62% acetonitrile in water and 0.05% hydrochloric acid) to afford (R)—N—((R)-2-((R)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (20 mg, 38%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.87 (s, 1H), 6.23 (s, 1H), 5.21-5.16 (m, 2H), 4.59-4.55 (m, 1H), 4.39-4.37 (m, 2H), 3.36 (s, 3H), 2.94-2.79 (m, 2H), 2.28-2.26 (m, 1H), 1.92-1.78 (m, 4H), 1.47 (s, 3H), 0.78 (t, J=6.8 Hz, 3H). LCMS R_(T)=0.84 min; m/z=446.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.84 min, ESI+ found [M+H]=446.2.

Example 325 WX Method XXXXX

(R)—N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide

A mixture of (S)-6-amino-2-((S)-2,2-difluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (30 mg, 0.12 mmol), (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (29 mg, 0.14 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.18 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (34 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium chloride in water) to give (R)—N—((S)-2-((S)-2,2-difluorocyclopropyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (20 mg, 38%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.87 (s, 1H), 6.21 (s, 1H), 5.20-5.16 (m, 2H), 4.58-4.53 (m, 1H), 4.38-4.27 (m, 2H), 3.35 (s, 3H), 2.98-2.78 (m, 2H), 2.27-2.17 (m, 1H), 1.92-1.78 (m, 4H), 1.46 (s, 3H), 0.76 (t, J=3.6 Hz, 3H). LCMS R_(T)=1.08 min; m/z=446.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.08 min, ESI+ found [M+H]=446.3.

Example 326 WX Method OO

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide

A mixture of 7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylic acid (20 mg, 0.10 mmol), (S)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (20 mg, 0.10 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (22 mg, 0.11 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (16 mg, 0.11 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 31-61%/0.05% NH₄OH in water) to afford N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-ethyl-7-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide (29.0 mg, 77%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 6.13 (s, 1H), 5.18-5.12 (m, 2H), 4.62-4.57 (m, 1H), 4.34-4.25 (m, 2H), 3.35 (s, 3H), 2.97-2.92 (m, 1H), 2.32-2.27 (m, 4H), 1.99-1.85 (m, 2H), 1.49 (s, 3H), 0.80 (t, J=7.6 Hz, 3H). LCMS R_(T)=0.729 min; m/z=385.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.729 min, ESI+ found [M+H]=385.1.

Example 327 WX Method O

(S)-4-(1-hydroxycyclobutyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide

Step 1: 1-(2-chloro-4-pyridyl)cyclobutanol

To a solution of 2-chloro-4-iodopyridine (2.4 g, 10.0 mmol) in tetrahydrofuran (100 mL) was added isopropyl magnesium chloride (13.0 mL, 13.0 mmol, 1.0 M in tetrahydrofuran) at −45° C. over 5 mins under nitrogen. After stirred for 45 mins at −45° C., cyclobutanone (2.1 g, 30.0 mmol) was added. The mixture was allowed to warm to 25° C. and stirred for 15 h. The mixture was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (1×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 1-(2-chloro-4-pyridyl)cyclobutanol (500 mg, 27%) as colorless oil, used in the next step without further purification.

Step 2: methyl 4-(1-hydroxycyclobutyl)picolinate

A mixture of 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (80 mg, 0.11 mmol), triethylamine (331 mg, 3.27 mmol) and 1-(2-chloro-4-pyridyl)cyclobutanol (200 mg, 1.09 mmol) in methanol (10 mL) was stirred at 70° C. for 15 h under carbon oxide (35 psi). The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) affording methyl 4-(1-hydroxycyclobutyl)picolinate (120 mg, 53%) as a yellow solid: LCMS R_(T)=0.554 min; m/z=207.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.554 min, ESI+ found [M+H]⁺=207.8.

Step 3: 4-(1-hydroxycyclobutyl)picolinic acid

A mixture of methyl 4-(1-hydroxycyclobutyl)picolinate (60 mg, 0.29 mmol) and potassium hydroxide (32 mg, 0.58 mmol) in ethanol (4 mL) and water (1 mL) was stirred for 2 h at 25° C.

The organic solvent was removed under reduced pressure, and the aqueous layer was adjusted to pH=3 by addition of hydrochloric acid (1.0 M). The aqueous layer was concentrated under reduced pressure affording crude 4-(1-hydroxycyclobutyl)picolinic acid (100 mg, 100%) as a white solid, used in the next step without further purification.

Step 4: (S)-4-(1-hydroxycyclobutyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide

A mixture of 4-(1-hydroxycyclobutyl)picolinic acid (100.0 mg, 0.52 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (30.0 mg, 0.16 mmol), 1-hydroxybenzotriazole (25.0 mg, 0.19 mmol) and 1-(3-dimethylamino propyl)-3-ethylcarbodiimidehydrochloride (35.9 mg, 0.19 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) affording (S)-4-(1-hydroxycyclobutyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (30.0 mg, 36%) as a white solid: ¹H NMR (400 MHz, CD₃OD): δ 8.63 (d, J=5.6 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 7.72-7.70 (m, 1H), 7.46-7.44 (m, 1H), 7.35-7.24 (m, 3H), 5.06-4.99 (m, 1H), 4.67-4.63 (m, 1H), 4.43-4.38 (m, 1H), 3.43 (s, 3H), 2.52-2.36 (m, 4H), 2.14-2.01 (m, 1H), 1.89-1.78 (m, 1H). LCMS R_(T)=0.992 min; m/z=368.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.992 min, ESI+ found [M+H]⁺=368.2.

Example 328 WX Method E

(S)-4-(1-hydroxycyclopentyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide

Step 1: 1-(2-chloropyridin-4-yl)cyclopentanol

To a solution of 2-chloro-4-iodopyridine (5.0 g, 20.9 mmol) in tetrahydrofuran (100 mL) was added isopropylmagnesium chloride (1.0 M, 27.2 mL, 27.2 mmol) dropwise at −45° C. over 5 min. Stirring at −45° C. was continued for 45 min, cyclopentanone (5.3 g, 62.7 mmol) was added dropwise. The resulting mixture was allowed to warm to 25° C. and stirred for another 15 h before quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 1-(2-chloropyridin-4-yl) cyclopentanol (500 mg, 12%) as colorless oil. LCMS R_(T)=1.42 min; m/z=198.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide over 3.0 mins) retention time 1.42 min, ESI+ found [M+H]=198.1

Step 2: methyl 4-(1-hydroxycyclopentyl)picolinate

A mixture of 1-(2-chloropyridin-4-yl) cyclopentanol (100 mg, 0.5 mmol), triethylamine (154 mg, 1.5 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride) (37 mg, 0.05 mmol) in methanol (50 mL) was stirred at 70° C. for 15 h under the atmosphere of carbon oxide (35 psi). The reaction mixture was filtered and the filtrate was concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) affording methyl 4-(1-hydroxycyclopentyl)picolinate (80 mg, 71%) as light yellow oil, used in the next step without further purification.

Step 3: 4-(1-hydroxycyclopentyl)picolinic acid

A mixture of methyl 4-(1-hydroxycyclopentyl)picolinate (80 mg, 0.36 mmol) and potassium hydroxide (40 mg, 0.72 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH=4 by addition of hydrochloric acid (2.0 M). The mixture was concentrated under reduced pressure to afford crude 4-(1-hydroxycyclopentyl)picolinic acid (60 mg, 80%) as a yellow solid, used in the next step without further purification.

Step 4: (S)-4-(1-hydroxycyclopentyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (30.0 mg, 0.12 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (33.7 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (23.7 mg, 0.18 mmol) and 4-(1-hydroxycyclopentyl)picolinic acid (36.0 mg, 0.18 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonia hydroxide in water) affording (S)-4-(1-hydroxycyclopentyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)picolinamide (25.9 mg, 57.4%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.58 (d, J=5.2 Hz, 1H), 8.15 (s, 1H), 7.67-7.65 (m, 1H), 7.46-7.41 (m, 1H), 7.35-7.29 (m, 2H), 7.27-7.22 (m, 1H), 5.05-4.96 (m, 1H), 4.67-4.58 (m, 1H), 4.43-4.36 (m, 1H), 3.43 (s, 3H), 2.03-1.84 (m, 8H). LCMS R_(T)=1.03 min; m/z=382.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.03 min, ESI+ found [M+H]=382.2.

Example 329 WX Method YY

(R)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxamide

A mixture of 5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylic acid (82 mg, 0.37 mmol), (6R)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (60 mg, 0.31 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (63 mg, 0.46 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (83 mg, 0.46 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 12-42%/0.05% ammonia hydroxide in water) to afford (R)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxamide (17.5 mg, 14%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.31-7.27 (m, 2H), 7.06-6.99 (m, 2H), 6.10 (s, 1H), 4.54-4.49 (m, 1H), 4.30-4.28 (m, 2H), 4.13 (s, 2H), 3.30 (s, 3H), 2.86-2.80 (m, 1H), 2.27-2.21 (m, 4H). LCMS R_(T)=0.735 min; m/z=398.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.735 min, ESI+ found [M+H]=398.1.

Example 330 WX Method JJJJJ

(S)-5-(4-fluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1, 3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

A mixture of 5-[(3-fluorophenyl)methyl]-4H-1,2,4-triazole-3-carboxylic acid (76 mg, 0.35 mmol), (6S)-6-amino-2,3,4-trimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (60 mg, 0.29 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (58 mg, 0.43 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (78 mg, 0.43 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 15-45%/0.05% ammonia hydroxide in water) to afford (S)-5-(4-fluorobenzyl)-N-(2,3,4-trimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (29.5 mg, 25%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.28-7.27 (m, 2H), 7.05-7.01 (m, 2H), 4.43-4.38 (m, 1H), 4.22-4.20 (m, 2H), 4.13 (s, 2H), 3.30 (s, 3H), 2.80-2.73 (m, 1H), 2.19-2.17 (m, 4H), 2.00 (s, 3H). LCMS R_(T)=0.754 min; m/z=412.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% formic acid over 1.5 mins) retention time 0.754 min, ESI+ found [M+H]=412.1.

Example 331 WX Method CCCC

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-[(2,3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (26 mg, 0.11 mmol), (6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethyl propane-1,3-diamine hydrochloride (24 mg, 0.14 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (17-47% acetonitrile in water and 0.05% hydrogen chloride) to give (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2,3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (18.9 mg, 47%) as white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 7.33-7.26 (m, 1H), 7.19-7.18 (m, 2H), 6.34 (s, 1H), 5.63 (s, 2H), 4.73-4.69 (m, 1H), 4.48-4.36 (m, 2H), 3.31 (s, 3H), 2.90-2.84 (m, 1H), 2.41 (m, 1H), 2.03-2.01 (m, 1H), 1.16-1.14 (m, 2H), 0.93-0.91 (m, 2H). LCMS R_(T)=1.00 min; m/z=442.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.00 min, ESI+ found [M+H]=442.1.

Example 332 WX Method DDDD

(S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxamide

A mixture of 5-[(4-fluorophenyl)methyl]-4H-1,2,4-triazole-3-carboxylic acid (30 mg, 0.14 mmol), (6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.09 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (18 mg, 0.14 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (26 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (28-58% acetonitrile in water and 0.05% hydrogen chloride) to give (S)—N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxamide (23 mg, 57%) as white solid: ¹H NMR (400 MHz, CD₃OD): 7.35-7.32 (m, 2H), 7.11-7.07 (m, 2H), 6.16 (s, 1H), 4.62-4.57 (m, 1H), 4.41-4.23 (m, 4H), 3.33 (s, 3H), 2.90-2.79 (m, 1H), 2.37-2.29 (m, 1H), 1.99-1.93 (m, 1H), 1.05-1.03 (m, 2H), 0.87-0.78 (m, 2H). LCMS R_(T)=1.18 min; m/z=424.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.18 min, ESI+ found [M+H]⁺=424.1.

The compounds of Examples 333-338 and methods for their preparation are shown in Table 3 below.

Example 339

1-[(4-fluorophenyl)methyl]-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide Method B

(57 mg, 89% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.45-7.33 (m, 2H), 7.28-7.14 (m, 2H), 6.34 (d, J=2.0 Hz, 1H), 5.47 (s, 2H), 4.40-4.11 (m, 3H), 3.24 (s, 3H), 2.64-2.56 (m, 1H), 2.42-2.30 (m, 1H).

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.62 min, ESI+ found [M+H]=384.2.

Example 340

1-[(2,4-difluorophenyl)methyl]-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide Method B

(53 mg, 79% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.54-7.40 (m, 2H), 7.38-7.25 (m, 1H), 7.20-7.04 (m, 1H), 6.34 (d, J=2.0 Hz, 1H), 5.52 (s, 1H), 4.46-4.09 (m, 3H), 3.24 (s, 3H), 2.66-2.54 (m, 1H), 2.43-2.30 (m, 1H).

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.69 min, ESI+ found [M+H]=402.1.

Example 341

1-[(3,4-difluorophenyl)methyl]-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide Method B

(68 mg, 99% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.55 (d, J=7.8 Hz, 1H), 7.53-7.39 (m, 2H), 7.30-7.11 (m, 2H), 6.34 (d, J=2.0 Hz, 1H), 5.61 (s, 2H), 4.42-4.13 (m, 3H), 3.24 (s, 3H), 2.65-2.54 (m, 1H), 2.44-2.29 (m, 1H).

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.77 min, ESI+ found [M+H]=402.1.

Example 342

1-[(2,3-difluorophenyl)methyl]-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide Method B Method B

(52 mg, 78% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.55 (d, J=7.8 Hz, 1H), 7.58-7.35 (m, 3H), 7.30-7.04 (m, 1H), 6.34 (d, J=2.1 Hz, 1H), 5.48 (s, 2H), 4.43-4.12 (m, 3H), 3.24 (s, 3H), 2.63-2.56 (m, 1H), 2.44-2.30 (m, 1H).

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.69 min, ESI+ found [M+H]=402.1.

Example 343 Method GH1

1-[(2,6-difluorophenyl)methyl]-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: (S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

To a solution of (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1200 mg, 6.66 mmol, 1.0 equiv) in DMF (15 mL) was added 4H-1,2,4-triazole-3-carboxylic acid (904 mg, 8.0 mmol, 1.2 equiv), N,N-diisopropylethylamine (3.48 mL, 20.0 mmol, 3.0 equiv), and PYAOP (4159 mg, 7.66 mmol, 1.15 equiv) last. The reaction mixture was stirred overnight then concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording N(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (1500 mg, 82% yield) as a white solid used as is in the next step.

LCMS R_(T)=0.71 min [2 min method], m/z=256 [M+H]⁺.

Step 2: 1-[(2,6-difluorophenyl)methyl]-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

To a suspension of N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-4H-1,2,4-triazole-3-carboxamide (500 mg, 1.8 mmol, 1.0 equiv) in acetonitrile (10 mL) was added potassium carbonate (502 mg, 3.63 mmol, 2.0 equiv) followed by 2,6-difluorobenzyl bromide (465 mg, 2.18 mmol, 1.2 equiv). The reaction mixture was stirred for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by RP-HPLC affording 1-[(2,6-difluorophenyl)methyl]-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (348 mg, 48% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.57-7.44 (m, 2H), 7.23-7.10 (m, 2H), 6.33 (d, J=2.0 Hz, 1H), 5.56 (s, 2H), 4.42-4.09 (m, 3H), 3.24 (s, 3H), 2.65-2.53 (m, 1H), 2.42-2.30 (m, 1H). LCMS R_(T)=3.67 min [10 min method], m/z=402.2 [M+H]⁺.

Example 344

(5S)—N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5-(trifluoro methyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one and commercially available (S)-5-(trifluoromethyl)pyrrolidin-2-one according to Method G11. Yield of final step: 71%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J=7.9 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 6.34 (d, J=2.0 Hz, 1H), 5.49 (td, J=7.8, 6.9, 3.4 Hz, 1H), 4.44-4.26 (m, 2H), 4.20 (ddd, J=14.5, 12.7, 6.6 Hz, 1H), 3.25 (s, 3H), 3.15-2.92 (m, 3H), 2.82-2.70 (m, 1H), 2.65-2.54 (m, 1H), 2.44-2.32 (m, 1H). LCMS R_(T)=3.38 min [10 min method], m/z=384.1 [M+H]⁺.

Example 345

N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5-isopropyl-6,7-di hydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-3-amino-6-fluoro-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one and commercially available ethyl 5-methyl-4-oxo-hexanoate according to Method GH2. Yield of final step: 47%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.35 (dd, J=7.7, 5.2 Hz, 1H), 6.99 (dd, J=10.7, 1.8 Hz, 1H), 6.89 (s, 1H), 4.90-4.80 (m, 1H), 4.63-4.53 (m, 1H), 4.47 (dd, J=10.1, 7.3 Hz, 1H), 4.34 (dt, J=9.1, 4.9 Hz, 1H), 2.92-2.83 (m, 2H), 2.79-2.65 (m, 1H), 2.48-2.35 (m, 1H), 2.30 (s, 3H), 2.23-2.09 (m, 1H), 0.95 (dd, J=6.9, 1.5 Hz, 3H), 0.81 (dd, J=6.9, 0.9 Hz, 3H). LCMS R_(T)=4.76 min [10 min method], m/z=388.1 [M+H]⁺.

Example 346 Method GH2

5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: tert-butyl (2-isopropyl-5-oxopyrrolidin-1-yl)carbamate

To a solution of ethyl 5-methyl-4-oxo-hexanoate (1000 mg, 5.80 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was added acetic acid (10 mL, 174.5 mmol, 30 equiv) and tert-butyl carbazate (1151 mg, 8.71 mmol, 1.5 equiv). The reaction mixture was stirred for 16 h at 50° C. After cooling the mixture to RT, sodium cyanoborohydride was added (547 mg, 8.71 mmol, 1.5 equiv). The reaction mixture was further stirred 4 h at RT. After this time, the reaction was quenched with 10% Na₂HPO₄ (150 mL) and extracted with isopropyl acetate (3×100 mL). The combined organics were washed with 10% Na₂HPO₄ (2×150 mL), water and brine, dried over sodium sulfate, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording tert-butyl (2-isopropyl-5-oxopyrrolidin-1-yl)carbamate as a pale yellow oil (800 mg, 57% yield) used as is in the next step. LCMS R_(T)=1.20 min [2 min method], m/z=243 [M+H]⁺.

Step 2: 2-isopropyl-5-oxopyrrolidin-1-aminium 2,2,2-trifluoroacetate

To a solution of tert-butyl (2-isopropyl-5-oxopyrrolidin-1-yl)carbamate in dichloromethane (5 mL) was added trifluoroacetic acid (5 ml). The reaction mixture was stirred for 1.5 h at RT. Toluene (10 ml) was added, and the mixture was concentrated to dryness in vacuo. The residue was resuspended in toluene and concentrated to dryness two more times affording 2-isopropyl-5-oxopyrrolidin-1-aminium 2,2,2-trifluoroacetate as a colorless oil which was used immediately in the next step without purification. LCMS R_(T)=0.80 min [2 min method], m/z=143 [M+H]⁺ for C₇H₁₅N₂O.

Step 3: ethyl 5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of 2-isopropyl-5-oxopyrrolidin-1-aminium 2,2,2-trifluoroacetate (850 mg, 3.3 mmol, 1.0 equiv) in acetonitrile (10 mL) was added ethyl 2-ethoxy-2-imino-acetate (0.48 mL, 500 mg, 3.5 mmol, 1.1 equiv). The resulting mixture was stirred for 1 h at RT, and then subject to microwave irradiation at 160° C. for 50 mins. The reaction mixture was concentrated to dryness in vacuo, and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate as a pale yellow oil (102 mg, 14% yield) used as is in the next step. LCMS R_(T)=1.08 min [2 min method], m/z=224 [M+H]⁺.

Step 4: sodium 5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl 5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (106 mg, 0.47 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) was added 1M aqueous sodium hydroxide (0.5 mL, 1.0500 equiv). The reaction mixture was stirred for 1 h at 50° C., then was concentrated to dryness in vacuo affording sodium 5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate as a brown solid which was used immediately in the next step without purification. LCMS R_(T)=0.90 min [2 min method], m/z=196 [M+H]⁺ for C₉H₁₃N₃O₂.

Step 5: 5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

To a solution of (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (35 mg, 0.19 mmol, 1.0 equiv) in N,N-dimethylformamide (2 mL) was added sodium 5-isopropyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]tri azole-2-carboxylate (52 mg, 0.237 mmol, 1.22 equiv), N,N-diisopropylethylamine (0.102 mL, 0.58 mmol, 3.0 equiv), and PYAOP (127 mg, 0.23 mmol, 1.2 equiv). The reaction mixture was stirred overnight then concentrated to dryness in vacuo. The residue was purified by RP-HPLC affording 5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (68 mg, 98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J=11.1, 7.8 Hz, 1H), 7.49 (dd, J=2.0, 0.6 Hz, 1H), 6.34 (dd, J=2.0, 1.2 Hz, 1H), 4.45-4.24 (m, 3H), 4.24-4.11 (m, 1H), 3.25 (d, J=1.5 Hz, 3H), 2.92-2.81 (m, 2H), 2.78-2.54 (m, 2H), 2.46-2.28 (m, 2H), 2.15 (pd, J=6.8, 4.7 Hz, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.81 (dd, J=6.8, 1.6 Hz, 3H). LCMS R_(T)=3.71 min [10 min method], m/z=358.2 [M+H]⁺.

Example 347

(5S)—N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-3-amino-6-fluoro-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one and commercially available (S)-5-(trifluoromethyl)pyrrolidin-2-one according to Method G11. Yield of final step: 57%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 6.99 (ddd, J=10.7, 1.8, 0.8 Hz, 1H), 6.90 (s, 1H), 5.58-5.43 (m, 1H), 4.86 (dt, J=11.1, 7.5 Hz, 1H), 4.60 (dd, J=11.2, 10.1 Hz, 1H), 4.46 (dd, J=10.1, 7.3 Hz, 1H), 3.16-2.96 (m, 3H), 2.84-2.70 (m, 1H), 2.35-2.27 (m, 3H). LCMS R_(T)=4.60 min [10 min method], m/z=414.1 [M+H]⁺.

Example 348

(5S)—N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one and commercially available (S)-5-(trifluoromethyl)pyrrolidin-2-one according to Method G11. Yield of final step: 84%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=7.7 Hz, 1H), 7.24 (ddd, J=10.4, 9.1, 2.9 Hz, 1H), 7.04 (ddd, J=9.4, 2.9, 1.8 Hz, 1H), 5.57-5.44 (m, 1H), 4.92 (dt, J=11.1, 7.4 Hz, 1H), 4.66 (dd, J=11.1, 10.2 Hz, 1H), 4.52 (dd, J=10.2, 7.1 Hz, 1H), 3.15-2.97 (m, 4H), 2.83-2.71 (m, 1H). LCMS R_(T)=4.34 min [10 min method], m/z=418.1 [M+H]⁺.

Example 349

5-ethyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-3-amino-6-fluoro-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one and commercially available ethyl 4-oxo-hexanoate according to Method GH2. Yield of final step: 23%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.35 (dd, J=7.8, 2.7 Hz, 1H), 6.98 (ddd, J=10.7, 1.8, 0.8 Hz, 1H), 6.89 (s, 1H), 4.90-4.79 (m, 1H), 4.58 (ddd, J=11.2, 10.1, 5.5 Hz, 1H), 4.46 (ddd, J=10.1, 7.3, 1.8 Hz, 1H), 4.43-4.34 (m, 1H), 2.93-2.76 (m, 3H), 2.37-2.31 (m, 1H), 2.30 (t, J=0.7 Hz, 3H), 1.96-1.83 (m, 1H), 1.78-1.64 (m, 1H), 0.91 (td, J=7.4, 1.0 Hz, 3H). LCMS R_(T)=4.44 min [10 min method], m/z=374.1 [M+H]⁺.

Example 350

(5S)—N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one and commercially available (S)-5-(trifluoromethyl)pyrrolidin-2-one according to Method G11. Yield of final step: 84%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=8.0 Hz, 1H), 7.55-7.47 (m, 1H), 7.38-7.20 (m, 3H), 5.56-5.44 (m, 1H), 4.84 (dt, J=11.5, 7.8 Hz, 1H), 4.59 (dd, J=11.5, 9.9 Hz, 1H), 4.42 (dd, J=9.9, 7.7 Hz, 1H), 3.32 (s, 3H), 3.12-2.97 (m, 3H), 2.81-2.71 (m, 1H). LCMS R_(T)=4.86 min [10 min method], m/z=396.1 [M+H]⁺.

Example 351

5-ethyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-di hydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one and commercially available ethyl 4-oxo-hexanoate according to Method GH2. Yield of final step: 77%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (t, J=7.5 Hz, 1H), 7.49 (dd, J=2.0, 0.5 Hz, 1H), 6.34 (dd, J=2.1, 0.8 Hz, 1H), 4.43-4.12 (m, 4H), 3.25 (d, J=1.5 Hz, 3H), 2.94-2.76 (m, 3H), 2.69-2.54 (m, 1H), 2.45-2.27 (m, 2H), 1.95-1.83 (m, 1H), 1.78-1.63 (m, 1H), 0.91 (td, J=7.4, 1.0 Hz, 3H). LCMS R_(T)=3.87 min [10 min method], m/z=344.2 [M+H]⁺.

Examples 352 and 354 Method GH_chiral_1

(5S)-5-isopropyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (5R)-5-isopropyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5-isopropyl-6,7-di hydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide was further purified by chiral SFC (SFC conditions: Column: Regis Whelk 0-1 (s,s)50×4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 45% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar) affording arbitrarily assigned diastereomers (5S)-5-isopropyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.008 g, 10%) and (5R)-5-isopropyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.008 g, 10%).

Analytical data for the first eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T) (Whelk 0-1 (S,S) column, 45% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.57 min, 100% ee: 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.36 (d, J=7.7 Hz, 1H), 6.99 (dd, J=10.9, 1.8 Hz, 1H), 6.89 (d, J=1.8 Hz, 1H), 4.85 (dt, J=11.1, 7.5 Hz, 1H), 4.58 (t, J=10.7 Hz, 1H), 4.47 (dd, J=10.1, 7.3 Hz, 1H), 4.34 (dt, J=9.0, 4.8 Hz, 1H), 2.92-2.82 (m, 2H), 2.79-2.64 (m, 1H), 2.42 (dtd, J=15.0, 8.7, 8.2, 4.8 Hz, 1H), 2.30 (s, 3H), 2.22-2.08 (m, 1H), 0.95 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H). LCMS R_(T)=5.12 min, m/z=388.2 [M+H]⁺.

Analytical data for the second eluting diastereomer (arbitrarily assigned S,R configuration): SFC R_(T) 0.85 min, 99% ee. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.35 (d, J=7.7 Hz, 1H), 6.99 (ddd, J=10.8, 1.9, 0.8 Hz, 1H), 6.89 (dt, J=1.9, 1.0 Hz, 1H), 4.85 (dt, J=11.0, 7.5 Hz, 1H), 4.57 (dd, J=11.1, 10.1 Hz, 1H), 4.47 (dd, J=10.1, 7.3 Hz, 1H), 4.34 (dt, J=8.4, 4.9 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 2.78-2.65 (m, 1H), 2.47-2.36 (m, 1H), 2.33-2.28 (m, 3H), 2.21-2.09 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H) LCMS R_(T)=5.14 min, m/z=388.2 [M+H]⁺.

Example 353 Method GH_chiral_2

(5R)-5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (5S)-5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide was further purified by chiral SFC (SFC conditions: Column: Regis Whelk 0-1 (s,s)50×4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 45% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar) affording arbitrarily assigned diastereomers (5R)-5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo][1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.018 g, 27%) and (5S)-5-isopropyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (0.019 g, 28%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned S,R configuration): SFC R_(T) (Whelk 0-1 (S,S) column, 45% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.90 min, 99% ee: 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=7.8 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 6.34 (d, J=2.0 Hz, 1H), 4.43-4.14 (m, 4H), 3.25 (s, 3H), 2.91-2.82 (m, 2H), 2.78-2.54 (m, 2H), 2.46-2.29 (m, 2H), 2.21-2.09 (m, 1H), 0.94 (d, J=6.9 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.18 min, m/z=358.2 [M+H]⁺.

Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T) 1.02 min, 99% ee. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=7.8 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 6.34 (d, J=2.0 Hz, 1H), 4.44-4.14 (m, 4H), 3.25 (s, 3H), 2.86 (t, J=7.5 Hz, 2H), 2.77-2.56 (m, 2H), 2.46-2.30 (m, 2H), 2.22-2.09 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.17 min, m/z=358.2 [M+H]⁺.

Example 355

5-ethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one and commercially available ethyl 4-oxo-hexanoate according to Method GH2. Yield of final step: 13%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J=8.0, 3.9 Hz, 1H), 7.54-7.47 (m, 1H), 7.37-7.21 (m, 3H), 4.88-4.77 (m, 1H), 4.56 (ddd, J=11.5, 9.9, 7.0 Hz, 1H), 4.46-4.34 (m, 2H), 3.31 (s, 3H), 2.93-2.75 (m, 3H), 2.39-2.27 (m, 1H), 1.96-1.82 (m, 1H), 1.77-1.63 (m, 1H), 0.91 (td, J=7.5, 1.1 Hz, 3H). LCMS R_(T)=4.28 min [10 min method], m/z=356.1 [M+H]⁺.

Example 356 Method GH3

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

Step 1: 6-bromo-1-(bromodifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

To a suspension of 6-bromo-1H-pyrazolo[4,3-c]pyridine (2000 mg, 10.1 mmol, 1.0 equiv) in acetonitrile (40 mL) was added cesium carbonate (9872 mg, 30.3 mmol, 3.0 equiv) and dibromodifluoromethane (1.85 mL, 4238 mg, 20.2 mmol, 2.0 equiv). The vessel was capped, and the reaction mixture was heated with vigorous stirring at 50° C. for 16 h. After this time, the mixture was diluted with dichloromethane and filtered through Celite. The filtrate was concentrated to dryness in vacuo to obtain the product 6-bromo-1-(bromodifluoromethyl)-1H-pyrazolo[4,3-c]pyridine as a dark red solid that was used in the next step without further purification. LCMS R_(T)=1.45 min [2 min method], m/z=328 [M+H]⁺.

Step 2: 6-bromo-1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

To a suspension of 6-bromo-1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (crude from the previous step) in dichloromethane (100 mL) cooled to −78° C. was added silver tetrafluoroborate (2949 mg, 15.2 mmol, 1.5 equiv). The reaction mixture was allowed to warm to RT slowly overnight. After this time, the mixture was diluted with dichloromethane/methanol (1:1), filtered through Celite, and concentrated to dryness in vacuo affording 6-bromo-1-(trifluoromethyl)pyrazolo[4,3-c]pyridine (1700 mg, 63% yield) as a yellow solid that was used without further purification. LCMS R_(T)=1.34 min [2 min method], m/z=266 [M]⁺.

Step 3: methyl 1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

A high-pressure vessel with gas inlet was charged successively with 6-bromo-1-(trifluoromethyl)pyrazolo[4,3-c]pyridine (1700 mg, 6.4 mmol, 1.0 equiv), methanol (30 mL), triethylamine (8.9 mL, 64 mmol, 10 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (480 mg, 0.64 mmol, 0.10 equiv). The reactor was flushed once with carbon monoxide gas, then pressurized to 120 psi carbon monoxide. The reaction was heated to 80° C. for 16 h. After this time, the gas was released and the mixture was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording methyl 1-(trifluoromethyl)pyrazolo[4,3-c]pyridine-6-carboxylate (263 mg, 17% yield) as an off white solid. LCMS R_(T)=1.15 min [2 min method], m/z=246 [M+H]⁺.

Step 4: sodium 1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

To a solution of methyl 1-(trifluoromethyl)pyrazolo[4,3-c]pyridine-6-carboxylate (263 mg, 1.1 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) was added 1M sodium hydroxide (1.18 mL, 1.1 equiv). The reaction mixture was stirred for 2 h at 50° C., then was concentrated to dryness in vacuo affording sodium 1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate as a brown residue which was used directly in the next reaction without purification. LCMS R_(T)=0.90 min [2 min method], m/z=233 [M+H]⁺ for C₈H₄F₃N₃O₂.

Step 5: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (229 mg, 1 mmol) in N,N-dimethylformamide (2 mL) was added sodium 1-(trifluoromethyl)pyrazolo[4,3-c]pyridine-6-carboxylate (271 mg, 1.07 mmol, 1.07 equiv), N,N-diisopropylethylamine (0.523 mL, 3 mmol, 3 equiv), and PYAOP (651 mg, 1.2 mmol, 1.2 equiv). The reaction mixture was stirred for 16 h at RT. After this time, the mixture was concentrated to dryness in vacuo and purified by RP-HPLC affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide (303 mg, 75% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J=1.1 Hz, 1H), 9.12 (d, J=7.8 Hz, 1H), 8.94 (s, 1H), 8.21 (p, J=1.3 Hz, 1H), 7.52 (dd, J=7.4, 2.1 Hz, 1H), 7.39-7.23 (m, 3H), 4.93 (dt, J=11.3, 7.8 Hz, 1H), 4.66-4.48 (m, 2H), 3.35 (s, 3H). LCMS R_(T)=5.53 min [10 min method], m/z=406.1 [M+H]⁺.

Example 357

(5S)—N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from (S)-3-amino-7,9-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one and commercially available (S)-5-(trifluoromethyl)pyrrolidin-2-one according to Method G11. Yield of final step: 73%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.34 (d, J=7.5 Hz, 1H), 7.27 (ddd, J=10.1, 9.0, 2.8 Hz, 1H), 7.20-7.10 (m, 1H), 5.55-5.43 (m, 1H), 4.36 (dt, J=11.5, 7.8 Hz, 1H), 3.12-2.97 (m, 3H), 2.85-2.70 (m, 3H), 2.48-2.38 (m, 1H), 2.31-2.18 (m, 1H). LCMS R_(T)=4.30 min [10 min method], m/z=416.1 [M+H]⁺.

Examples 358 and 359 Method GH_chiral_3

(5R)-5-ethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (5S)-5-ethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

5-ethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazole-2-carboxamide was further purified by chiral SFC (SFC conditions: Column: CHIRALCEL OX 50×4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 35% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar) affording arbitrarily assigned diastereomers (5R)-5-ethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (5S)-5-ethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide.

Analytical data for the first eluting diastereomer (arbitrarily assigned S,R configuration): SFC R_(T) (CHIRALCEL-OX column, 35% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.80 min, 100% ee: 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J=8.0 Hz, 1H), 7.50 (dd, J=7.6, 2.0 Hz, 1H), 7.38-7.16 (m, 3H), 4.82 (dt, J=11.5, 7.8 Hz, 1H), 4.57 (dd, J=11.5, 9.9 Hz, 1H), 4.47-4.33 (m, 2H), 3.32 (s, 3H), 2.97-2.75 (m, 3H), 2.39-2.26 (m, 1H), 1.89 (ddd, J=13.9, 7.4, 5.2 Hz, 1H), 1.78-1.63 (m, 1H), 0.91 (t, J=7.4 Hz, 3H). LCMS R_(T)=4.45 min, m/z=356.1 [M+H]⁺.

Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T) 1.13 min, 99% ee. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=8.0 Hz, 1H), 7.54-7.46 (m, 1H), 7.38-7.20 (m, 3H), 4.83 (dt, J=11.5, 7.8 Hz, 1H), 4.55 (dd, J=11.4, 9.9 Hz, 1H), 4.46-4.33 (m, 2H), 3.32 (s, 3H), 2.92-2.76 (m, 3H), 2.38-2.25 (m, 1H), 1.88 (dtd, J=14.9, 7.4, 5.1 Hz, 1H), 1.70 (dt, J=14.0, 7.2 Hz, 1H), 0.91 (t, J=7.4 Hz, 3H). LCMS R_(T)=4.47 min, m/z=356.1 [M+H]⁺.

Example 360 Method GH4 & Method GH3

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: methyl 1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

A high-pressure vessel with gas inlet was charged successively with 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (1000 mg, 6.47 mmol, 1.0 equiv), 2-butanol (30 mL), triethylamine (9.0 mL, 64.7 mmol, 10.0 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (483 mg, 0.65 mmol, 0.10 equiv). The reactor was flushed once with carbon monoxide gas, then pressurized to 120 psi carbon monoxide. The reaction was heated to 80° C. for 16 h. After this time, the gas was released and the mixture was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording methyl 1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (470 mg, 41% yield) as a yellow solid. Note that the initially formed sec-butyl ester was transesterified to the methyl ester during chromatography. LCMS R_(T)=0.84 min [2 min method], m/z=179 [M+H]⁺.

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)pyrazolo[3,4-d]pyrimidine-6-carboxamide

The remainder of the synthesis was completed using methyl 1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate according to Method GH3 Steps 1,2,4, and 5. Yield of final step: 15%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.15 (d, J=7.7 Hz, 1H), 8.92 (s, 1H), 7.57-7.50 (m, 1H), 7.39-7.24 (m, 3H), 4.91 (dt, J=10.9, 7.9 Hz, 1H), 4.64-4.50 (m, 2H), 3.35 (s, 3H). LCMS R_(T)=4.84 min [10 min method], m/z=407.1 [M+H]⁺.

Example 361 Method GH5 and Method GH2

5-(1-methylimidazol-2-yl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: ethyl 4-(methoxy(methyl)amino)-4-oxobutanoate

To a solution of N,O-dimethylhydroxylamine hydrochloride (4444.9 mg, 45.6 mmol, 1.5 equiv) in dichloromethane (100 mL) cooled to 0° C. was added triethylamine (12.7 mL, 91.1 mmol, 3.0 equiv) followed by ethyl 4-chloro-4-oxo-butanoate (4.329 mL, 5000 mg, 30.4 mmol, 1.0 equiv). The reaction mixture was stirred and allowed to warm to RT slowly overnight. After this time, water (100 mL) was added, the layers separated, and the aqueous extracted two more times with dichloromethane (2×100 mL). The combined organics were washed with 5% citric acid and brine, dried over sodium sulfate and concentrated to dryness in vacuo affording ethyl 4-[methoxy(methyl)amino]-4-oxo-butanoate (5100 mg, 89% yield) as a yellow oil that was used in the next step without further purification.

Step 2: ethyl 4-(1-methyl-1H-imidazol-2-yl)-4-oxobutanoate

To a solution of 1-methylimidazole (2200 mg, 27 mmol, 1.0 equiv) in tetrahydrofuran (100 mL) cooled to 0° C. was added N-butyllithium (2.5 M in hexanes, 11 mL, 27 mmol, 1.0 equiv) dropwise. The reaction mixture was stirred 30 mins at 0° C., then was cooled to −78° C. To the mixture was added ethyl 4-[methoxy(methyl)amino]-4-oxo-butanoate (5100 mg, 27 mmol, 1.0 equiv). The resulting mixture was stirred for 1 h at −78° C., then allowed to warm to RT. After reaching RT, the reaction was quenched with 5% citric acid (150 mL), then extracted with isopropyl acetate (3×100 mL). The combined organics were washed with water and brine, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording ethyl 4-(1-methylimidazol-2-yl)-4-oxo-butanoate (1200 mg, 21% yield) as a yellow oil.

5-(1-methylimidazol-2-yl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

The title compound was prepared from ethyl 4-(1-methylimidazol-2-yl)-4-oxo-butanoate and dihydrobenzo[b][1,4]oxazepin-4(5H)-one according to Method GH2. Yield of final step: 53%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (dd, J=8.0, 5.7 Hz, 1H), 7.54-7.45 (m, 1H), 7.36-7.18 (m, 4H), 6.84 (d, J=1.1 Hz, 1H), 5.91-5.80 (m, 1H), 4.80 (dt, J=11.4, 7.8 Hz, 1H), 4.55 (ddd, J=11.7, 9.9, 2.2 Hz, 1H), 4.39 (ddd, J=9.9, 7.7, 4.4 Hz, 1H), 3.79 (d, J=0.8 Hz, 3H), 3.31 (s, 3H), 3.19-2.95 (m, 4H). LCMS R_(T)=2.70 min [10 min method], m/z=408.1 [M+H]⁺.

Example 364 Method CS1

1-benzyl-N-[(1R,4S,7S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[5.1.0]octan-4-yl]-1,2,4-triazole-3-carboxamide

Step 1: 2-((4S)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)isoindoline-1,3-dione

A solution of sodium chlorodifluoroacetate (1.42 g, 9.25 mmol) in diglyme (5.9 mL) was added dropwise to a refluxing solution of 2-[(3S)-1-methyl-2-oxo-4,5-dihydro-3H-azepin-3-yl]isoindoline-1,3-dione (0.250 g, 0.925 mmol) in diglyme (10 mL) over 25 minutes. After addition, the reaction was allowed to stir for an additional 10 minutes at reflux. After cooling to rt, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica, 0% to 70% isopropyl acetate-heptane) to give 2-[(4S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[5.1.0]octan-4-yl]isoindoline-1,3-dione (0.270 g, 0.843 mmol, 91% yield) as an inseparable ˜6.8:1 mixture of diastereomers. ¹H NMR (400 MHz, Chloroform-d) 6 (major isomer) 7.90-7.81 (m, 2H), 7.75-7.70 (m, 2H), 5.44 (dd, J=11.6, 8.0 Hz, 1H), 3.66-3.30 (m, 1H), 3.26-3.11 (m, 1H), 3.02 (s, 3H), 2.25-2.15 (m, 1H), 2.04-1.90 (m, 2H), 1.85-1.72 (m, 1H). LRMS R_(T)=1.29 min, m/z=321 [M=H]⁺.

Step 2: 1-benzyl-N-[(1R,4S,7S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[5.1.0]octan-4-yl]-1,2,4-triazole-3-carboxamide

Hydrazine (0.087 mL, 2.72 mmol) was added to a solution of 2-[(4S)-8,8-difluoro-6-methyl-5-oxo-6-azabicyclo[5.1.0]octan-4-yl]isoindoline-1,3-dione and (˜6.8:1 dr, 0.290 g, 0.905 mmol) in ethanol (9.1 mL). The reaction was heated at 80° C. for 2 h. After cooling to rt, the reaction was filtered through a short plug of celite using ethanol. The filtrate was evaporated which delivered (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo[5.1.0]octan-5-one (88.9 mg, 0.467 mmol, 51.6% Yield). The crude residue was used in the next step without further purification. PYAOP (0.138 g, 0.254 mmol) was added to a solution of (4S)-4-amino-8,8-difluoro-6-methyl-6-azabicyclo[5.1.0]octan-5-one (44 mg, 0.231 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (58 mg, 0.289 mmol), and N,N-diisopropylethylamine (0.120 mL, 0.694 mmol), in N,N-dimethylformamide (2.3 mL). The reaction was allowed to stir at rt for 18 h before being concentrated under reduced pressure. The crude residue was purified by preparative HPLC (see below) to give 1-benzyl-N-((1S,4S,7R)-8,8-difluoro-2-methyl-3-oxo-2-azabicyclo[5.1.0]octan-4-yl)-1H-1,2, 4-triazole-3-carboxamide (56.7 mg, 0.151 mmol, 65% Yield).

¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.58 (d, J=4.4 Hz, 1H), 7.43-7.27 (m, 5H), 5.48 (s, 2H), 4.43-4.33 (m, 1H), 3.27-3.14 (m, 1H), 2.80 (s, 3H), 2.55-2.43 (m, 1H), 2.10-2.00 (m, 3H), 1.30-1.10 (m, 1H).

LRMS R_(T)=3.90 min, m/z=376.1 [M+H]⁺.

Prep HPLC Information: Column: Phenomenex Gemini-NX C18 5 □m, 110 A (50×30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A)/Acetonitrile (B) Elution Program Gradient: 20 to 60% B Pressure: 800 psi

Flow Rate: 60 mL/min

Column Temperature: 25° C. Wavelength: 210 nm Example 365 Method CS2

1-benzyl-N-(2-isopropenyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide

Step 1: 2-bromo-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

Iodotrimetheylsilane (7.10 g, 34 mmol) was added to a solution of 2-bromo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.4 g, 5.7 mmol) and N,N,N′,N′-tetramethylethylenediamine (5.2 mL, 34 mmol) in dichloromethane (57 mL) at −15° C. After 1 h 30 minutes, iodine (4.4 g, 17 mmol) was added and the reaction was allowed to stir for an additional 2 h. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to the reaction. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, concentrated and the residue was purified by column chromatography (silica, 0% to 60% isopropyl acetate-heptane) to give 2-bromo-6-iodo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.56 g, 4.22 mmol, 74% Yield).

¹H NMR (400.33 MHz, Chloroform-d) 66.13 (s, 1H), 4.65 (ddd, J=8.6, 7.4, 3.4 Hz, 1H), 4.36-4.14 (m, 2H), 3.33 (s, 3H), 2.95 (ddt, J=14.4, 8.7, 7.4 Hz, 1H), 2.77 (dddd, J=14.4, 8.6, 6.6, 5.0 Hz, 1H).

Step 2: tert-butyl (2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

Sodium azide (0.319 g, 4.87 mmol) was added to a solution of 2-bromo-6-iodo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.50 g, 4.05 mmol) in N,N-dimethylformamide (16.2 mL) at rt. The reaction was allowed to stir at rt for 1 h. The solvent was removed under vacuum and the residue was submitted to the next step immediately without any further purification.

Triphenylphosphine (2.15 g, 8.11 mmol) was added to a solution of 6-azido-2-bromo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one in tetrahydrofuran (40.5 mL) and water (2.0 mL). The reaction was heated at 55° C. for 1 h. After cooling to rt the volatiles were removed under vacuum. The residue was dissolved in dichloromethane (40.5 mL), then triethylamine (2.85 mL, 20.3 mmol) and di-tert-butyl dicarbonate (2.23 g, 10.1 mmol) were added sequentially. After 1 h, the volatiles were removed under vacuum and the residue was purified by column chromatography (silica, 20% to 100% isopropyl acetate-heptane) to give tert-butyl N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (1.29 g, 3.59 mmol, 89% yield).

LRMS R_(T)=1.34 min m/z=304 M−C₄H₉+H]⁺.

Step 3. tert-butyl (2-acetyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carba mate

Bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.033 mmol) was added to a solution of tert-butyl N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (0.20 g, 0.56 mmol) and tributyl(1-ethoxyvinyl)tin (0.19 mL, 0.56 mmol) in 1,4-dioxane (10 mL). The flask was sealed with a yellow cap and heated at 100° C. for 12 h. Silica gel was added and the reaction was evaporated under reduced pressure. The crude material was purified by flash column chromatography (silica, 0% to 100% isopropyl acetate-heptane) to give tert-butyl N-(2-acetyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (0.120 g, 0.372 mmol, 100 mass %, 67% Yield).

¹H NMR (400.33 MHz, Chloroform-d) δ 6.58 (s, 1H), 5.43 (d, J=7.7 Hz, 1H), 4.46 (dd, J=14.4, 8.2 Hz, 1H), 4.33-4.03 (m, 2H), 3.35 (s, 3H), 3.06-2.88 (m, 1H), 2.56 (s, 3H), 2.02 (s, 1H), 1.41 (s, 9H).

LRMS R_(T)=1.34 min, m/z=267 [M−C₄H9+H]⁺.

Step 4 1-benzyl-N-(2-isopropenyl-4-methyl-5-oxo-7,8-dihydro-6-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide

Methylmagnesium bromide ((1.4 mol/L) in THF: toluene (1:3), 1.60 mL, 2.23 mmol) was added to a solution of tert-butyl N-(2-acetyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (0.120 g, 0.372 mmol) in tetrahydrofuran (3.7 mL) at −10° C. After 2 h, the reaction was quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with isopropyl acetate (3×30 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, concentrated, and the residue was submitted to the next step without further purification.

Trifluoroacetic acid (1.0 mL, 13 mmol, 99 mass %) was added to a solution of the crude tert-butyl N-[2-(1-hydroxy-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[[1,5-a][1,3]diazepin-6-yl]carbamate (50 mg 0.148 mmol) in dichloromethane (2.0 mL) at 0° C. After 10 min the reaction was warmed to rt and stirred for an additional 30 min. The solvent was removed under reduced pressure and the residue was submitted to the next reaction without further purification.

PYAOP (88.3 mg, 0.163 mmol) was added to a solution of the crude residue, 1-benzyl-1,2,4-triazole-3-carboxylic acid (37.5 mg, 0.185 mmol), and N,N-diisopropylethylamine (0.08 mL, 0.443 mmol), in N,N-dimethylformamide (1.5 mL, 19.1 mmol). The reaction was allowed to stir at rt for 18 h. The reaction was concentrated and the residue was purified by preparative HPLC (see below) to give 1-benzyl-N-(2-isopropenyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide (25 mg, 0.0617 mmol, 41.7% Yield) ¹H NMR (400.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.54 (d, J=7.9 Hz, 1H), 7.47-7.18 (m, 5H), 6.59 (s, 1H), 5.56-5.43 (m, 3H), 5.06 (t, J=1.7 Hz, 1H), 4.42-4.28 (m, 2H), 4.28-4.09 (m, 1H), 3.25 (s, 3H), 2.72-2.53 (m, 1H), 2.38 (dd, J=12.5, 6.4 Hz, 1H), 2.04 (s, 3H).

LRMS R_(T)=4.47 min, m/z=406.2 [M+H]⁺.

Prep HPLC Information: Column: Phenomenex Gemini-NX C18 5 □m, 110 A (50×30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A)/Acetonitrile (B) Elution Program Gradient: 20-60 B Pressure: 800 psi

Flow Rate: 20 mL/min

Column Temperature: 25° C. Wavelength: 254 nm Example 366 Method CS3

(S)—N-(2-acetyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-benzyl-1H-1,2,4-triazole-3-carboxamide

Step 1: (S)—N-(2-acetyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-benzyl-1H-1,2,4-triazole-3-carboxamide

Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl N-[2-(1-ethoxyvinyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (0.550 g, 1.57 mmol) in dichloromethane (20 mL) at rt. After 2 h the solvent was removed under reduced pressure and the residue was submitted to the next reaction without further purification.

N,N-diisopropylethylamine (0.82, 4.71 mmol) was added to a solution of the crude residue, 1-benzyl-1,2,4-triazole-3-carboxylic acid (0.319 g, 1.57 mmol), and PYAOP (0.852 g, 1.57 mmol) in N,N-dimethylformamide (15.7 mL) at rt. After 3 h the solvent was removed under reduced pressure. A portion of the crude residue (200 mg) was purified by preparative HPLC (see below) to give (S)—N-(2-acetyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-benzyl-1H-1,2,4-triazole-3-carboxamide (15.7 mg, 0.0385 mmol).

¹H NMR (400.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.59 (d, J=7.7 Hz, 1H), 7.43-7.26 (m, 5H), 6.83 (s, 1H), 5.48 (s, 2H), 4.48 (dd, J=14.5, 7.9 Hz, 1H), 4.41-4.26 (m, 2H), 3.26 (s, 3H), 2.72-2.57 (m, 1H), 2.48 (s, 3H), 2.52-2.40 (m, 1H).

LRMS R_(T)=3.84 min, m/z=408.2 [M+H]⁺.

Prep HPLC Information: Column: Phenomenex Cellulose-3, 5 □m (150×21.2 mm) Mobile Phase: Carbon Dioxide (A)/0.1% NH₄OH in Methanol (B) Elution Program Gradient: Isocratic @ 35% Pressure: 100 bar

Flow Rate: 70 mL/min

Column Temperature: 40° C. Wavelength: 220 nm Examples 367 and 368 Method CS4

1-benzyl-N-((6S)-2-(1-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 1-benzyl-N-((6S)-2-(1-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Sodium borohydride (56.9 mg, 1.47 mmol) was added to a solution of N-(2-acetyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-benzyl-1,2, 4-triazole-3-carboxamide (0.300 g (crude), 0.736 mmol) in methanol (4.1 mL) at 0° C. After 5 min, saturated aqueous ammonium chloride was added. The aqueous layer was extracted with isopropyl acetate (5×40 mL). The combined organic layers were washed with brine, dried with sodium sulfate, concentrated, and the residue was purified by preparative HPLC (see below) to give 1-benzyl-N-((6 S)-2-(1-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (Peak 1, 9.4 mg, 0.023 mmol, 3.1% Yield) and 1-benzyl-N-((6 S)-2-(1-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (Peak 2, 9.1 mg, 0.022 mmol, 3.0% yield).

Data for Example 367

¹H NMR (400.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.43-7.27 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 5.08 (d, J=5.1 Hz, 1H), 4.69-4.58 (m, 1H), 4.38-4.24 (m, 2H), 4.20-4.07 (m, 1H), 3.23 (s, 3H), 2.64-2.45 (m, 1H), 2.39-2.29 (m, 1H), 1.38 (d, J=6.5 Hz, 3H).

LRMS R_(T)=3.44 min, m/z=410.2 [M+H]⁺.

Data for Example 368

¹H NMR (400.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.51 (d, J=7.9 Hz, 1H), 7.43-7.26 (m, 5H), 6.27 (s, 1H), 5.48 (s, 2H), 5.16 (d, J=4.5 Hz, 1H), 4.72-4.61 (m, 1H), 4.40-4.23 (m, 2H), 4.21-4.07 (m, 1H), 3.24 (s, 3H), 2.64-2.50 (m, 1H), 2.39-2.29 (m, 1H), 1.34 (d, J=6.5 Hz, 3H).

LRMS R_(T)=3.48 min, m/z=410.2 [M+H]⁺.

Prep HPLC Information: Stage 1: Column: Chiralcel OX, 5 □m (150×21.2 mm) Mobile Phase: Carbon Dioxide (A)/0.1% NH₄OH in Methanol (B) Elution Program Gradient: Isocratic @ 50% Pressure: 100 bar

Flow Rate: 70 mL/min

Column Temperature: 40° C. Wavelength: 220 nm Stage 2: Column: Chiralpak AD, 5 □m (150×21.2 mm) Mobile Phase: Carbon Dioxide (A)/0.1% NH₄OH in Methanol (B) Elution Program Gradient: Isocratic @ 50% Pressure: 100 bar

Flow Rate: 70 mL/min

Column Temperature: 40° C. Wavelength: 220 nm Examples 369 and 370 Method CS5

1-benzyl-N-[2-(1-fluoro-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[2-(1-fluoro-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: 1-benzyl-N-[2-(1-fluoro-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[2-(1-fluoro-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Bis(2-methoxyethyl)aminosulfur trifluoride (63.3 mg, 0.283 mmol) was added to a solution of 1-benzyl-N-[2-(1-hydroxy-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (30 mg, 0.071 mmol) in dichloromethane (0.71 mL) at 0° C. After 10 min the reaction was carefully quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried with sodium sulfate, concentrated, and the residue was purified by preparative HPLC (see below) to give 1-benzyl-N-[2-(1-fluoro-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, 10.9 mg, 0.0256 mmol, 36.2% Yield) and 1-benzyl-N-[2-(1-fluoro-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, 11.9 mg, 0.028 mmol, 39.5% Yield)

Data for G03074389:

Peak 1: ¹H NMR (400 0.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.55 (d, J=7.8 Hz, 1H), 7.43-7.27 (m, 5H), 6.48 (s, 1H), 5.48 (s, 2H), 4.40-4.24 (m, 2H), 4.25-4.13 (m, 1H), 3.25 (s, 3H), 2.66-2.54 (m, 1H), 2.44-2.32 (m, 1H), 1.71 (d, 7.7 Hz, 3H), 1.66 (d, 7.7 Hz, 3H).

LRMS R_(T)=4.47 min, m/z=426.3 [M+H]⁺.

Data for G03074390:

Peak 2: ¹H NMR (400.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.55 (d, J=7.8 Hz, 1H), 7.43-7.27 (m, 5H), 6.48 (s, 1H), 5.48 (s, 2H), 4.40-4.27 (m, 2H), 4.25-4.13 (m, 1H), 3.25 (s, 3H), 2.66-2.53 (m, 1H), 2.44-2.32 (m, 1H), 1.71 (d, 7.7 Hz, 3H), 1.66 (d, 7.7 Hz, 3H).

LRMS R_(T)=4.47 min, m/z=426.3 [M+H]⁺.

Column: Phenomenex Cellulose-3, 5 □m, (150×21.2 mm)

Mobile Phase: Carbon Dioxide (A)/Neat methanol (B)

Elution Program Gradient: Isocratic @ 40% Pressure: 100 bar

Flow Rate: 70 mL/min

Column Temperature: 40° C. Wavelength: 220 nm Example 371 Method CS6

1-benzyl-N-[2-(1,1-difluoroethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1,2,4-triazole-3-carboxamide Step 1: 1-benzyl-N-[2-(1,1-difluoroethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1,2,4-triazole-3-carboxamide

Diethylaminosulfur trifluoride (2.73 mL, 19.64 mmol) was added to a solution of N-(2-acetyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-benzyl-1,2, 4-triazole-3-carboxamide (0.400 g (crude), 0.982 mmol) in dichloromethane (2.0 mL). The reaction was heated at 40° C. for 8 h. After, the reaction was carefully poured into a solution of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with isopropyl acetate (4×50 mL). The combined organic layers were washed with brine, dried with sodium sulfate, concentrated, and the residue was purified by preparative HPLC (see below) to give 1-benzyl-N-[2-(1,1-difluoroethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (16.8 mg, 0.039 mmol, 3.98% Yield)

¹H NMR (400.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.59 (d, J=7.7 Hz, 1H), 7.43-7.26 (m, 5H), 6.65 (s, 1H), 5.48 (s, 2H), 4.45-4.19 (m, 3H), 3.26 (s, 3H), 2.71-2.54 (m, 1H), 2.51-2.36 (m, 1H), 2.00 (t, J=18.8 Hz, 3H).

LRMS R_(T)=4.55 min, m/z=430.2 [M+H]⁺.

Column: Es Industries Pyridyl Amide (150×21.2 mm)

Mobile Phase: Carbon Dioxide (A)/Neat methanol (B)

Elution Program Gradient: Isocratic @ 20% Pressure: 100 bar

Flow Rate: 70 mL/min

Column Temperature: 40° C. Wavelength: 220 nm Example 372 Method CS7

1-benzyl-N-[2-(1-hydroxy-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide Step 1: 1-benzyl-N-[2-(1-hydroxy-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Methylmagnesium bromide ((1.4 mol/L) in THF: Toluene (1:3), 2.5 mL, 3.44 mmol) was added to a solution of N-(2-acetyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-benzyl-1,2,4-triazole-3-carboxamide (0.350 g (crude), 0.859 mmol) in tetrahydrofuran (4.3 mL) at −50° C. After 45 min the reaction was quenched with methanol. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (see below) to give 1-benzyl-N-[2-(1-hydroxy-1-methyl-ethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (33.2 mg, 0.0784 mmol, 9.13% Yield)

¹H NMR (400.33 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52 (d, J=7.9 Hz, 1H), 7.43-7.25 (m, 5H), 6.28 (s, 1H), 5.48 (s, 2H), 4.97 (s, 1H), 4.39-4.25 (m, 2H), 4.20-4.07 (m, 1H), 3.23 (s, 3H), 2.60 (ddd, J=20.6, 7.8, 5.2 Hz, 1H), 2.34 (td, J=12.6, 6.6 Hz, 1H), 1.45 (s, 3H), 1.40 (s, 3H).

LRMS R_(T)=3.56 min, m/z=406.2 [M+H]⁺.

Column: Phenomenex Gemini-NX C18 5 □m, 110 A (50×30 mm) Mobile Phase: 0.1% Ammonium Hydroxide in Water (A)/Acetonitrile (B) Elution Program Gradient: 5-50 B Pressure: 800 psi

Flow Rate: 60 mL/min

Column Temperature: 25° C. Wavelength: 220 nm Example 373 Method GZ1

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (580 mg, 2.70 mmol), phenyl boronic acid (496 mg, 4.07 mmol), 2 M of sodium carbonate in water (2.72 ml, 5 mmol) in acetonitrile (9.4 mL) was degassed, and bis(triphenylphosphine)palladium(II) chloride (190 mg, 0.27 mmol) was added under nitrogen. The vial was capped and heated in a microwave to 130° C. for 25 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to afford 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (389 mg, 68%) as a tan solid, used in the next step without further purification. LCMS R_(T)=1.42 min, m/z=211 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.42 min, ESI+ found [M+H]=211.

Step 2: 2-iodo-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1050 mg, 4.99 mmol) and p-toluene sulphonic acid (3.65 g, 19.20 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (2.70 g, 16.00 mmol) and sodium nitrite (865 mg, 12.50 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×100) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 2-iodo-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine (780 mg, 49%) as a light yellow solid.

LCMS R_(T)=2.27 min, m/z=321.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 2.27 min, ESI+ found [M+H]=321.9.

Step 3: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Palladium(II) acetate (6.0 mg, 0.025 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21.6 mg, 0.037 mmol), 2-iodo-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine (80 mg, 0.25 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (47.9 mg, 0.25 mmol) were added to a screw-cap vial. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (5 mL), and triethylamine (0.226 mL, 1.62 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 100% isopropyl acetate in heptane) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-[1,2,4]triazol o[1,5-a]pyridine-2-carboxamide (98.0 mg, 95% Yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (d, J=7.8 Hz, 1H), 8.03-7.91 (m, 3H), 7.88 (m, 1H), 7.65-7.55 (m, 3H), 7.50 (ddd, J=14.5, 7.3, 1.7 Hz, 2H), 7.41-7.22 (m, 3H), 4.90 (dt, J=11.4, 7.8 Hz, 1H), 4.63 (dd, J=11.5, 9.9 Hz, 1H), 4.48 (dd, J=9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LCMS RT=5.10 min, m/z=414.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.10 min, ESI+ found [M+H]=414.1.

Example 374 Method GZ10

(S)-5-ethyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-ethyl-2-iodo-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-ethyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (800 mg, 4.93 mmol) and p-toluene sulphonic acid (3.60 g, 18.94 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (2.70 g, 16.23 mmol) and sodium nitrite (854 mg, 12.38 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×120 mL) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 5-ethyl-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (908 mg, 67%) as a light yellow solid. LC-MS R_(T)=1.80 min, m/z=273.9 (M+H)⁺

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.80 min, ESI+ found [M+H]=273.9.

Step 2: (S)-5-ethyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Palladium(II) acetate (8.0 mg, 0.037 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31.8 mg, 0.055 mmol), 5-ethyl-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.37 mmol), (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (66.0 mg, 0.37 mmol) were added to a screw-cap vial. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (5 mL), and triethylamine (0.33 mL, 2.38 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial, with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% dicholormethane in methanol) to afford (S)-5-ethyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (80.0 mg, 62% Yield) as a tan solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=7.8 Hz, 1H), 7.85-7.71 (m, 2H), 7.51 (d, J=2.0 Hz, 1H), 7.20 (dq, J=7.3, 1.2 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H), 4.46-4.33 (m, 2H), 4.23 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 3.45-3.23 (m, 3H), 3.25-3.11 (m, 2H), 2.67 (tt, J=12.9, 8.1 Hz, 1H), 2.44 (td, J=12.3, 6.5 Hz, 1H), 1.37 (t, J=7.5 Hz, 3H). LC-MS R_(T)=3.51 min, m/z=354.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.51 min, ESI+ found [M+H]=354.2

Example 375

(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one according to Method GZ1. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid). Yield of final step: 52.8 mg, 42%: ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (d, J=7.7 Hz, 1H), 8.04-7.83 (m, 4H), 7.65-7.54 (m, 3H), 7.53-7.44 (m, 2H), 6.36 (d, J=2.0 Hz, 1H), 4.45-4.31 (m, 2H), 4.22 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 3.39-3.19 (m, 3H), 2.76-2.59 (m, 1H), 2.42 (m, 1H). LC-MS R_(T)=4.12 min, m/z=402.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.12 min, ESI+ found [M+H]=402.1

Example 376 Method GZ2

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-[1,2,4]triazol o[1,5-a]pyridine-2-carboxamide (40 mg, 0.097 mmol) in acetic acid (1 mL) was added platinum(iv) oxide (3 mg, 0.0096 mmol, 0.10 equiv). The reaction mixture stirred under a balloon of hydrogen gas for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7,8-tetra hydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (16 mg, 40%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (t, J=8.0 Hz, 1H), 7.49 (dt, J=7.5, 1.7 Hz, 1H), 7.40-7.18 (m, 6H), 7.09-7.01 (m, 2H), 5.57 (t, J=5.8 Hz, 1H), 4.80 (dtd, J=11.6, 7.8, 2.3 Hz, 1H), 4.57 (ddd, J=11.5, 9.9, 8.0 Hz, 1H), 4.38 (dd, J=9.9, 7.7 Hz, 1H), 3.44-3.17 (m, 3H), 3.01 (m, 2H), 2.45-2.32 (m, 1H), 2.10-1.99 (m, 1H), 1.92-1.82 (m, 2H). LC-MS R_(T)=4.87 min, m/z=418.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.87 min, ESI+ found [M+H]=418.2.

Example 377 Method GZ3

5-cyclohexyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-[1,2,4]triazol o[1,5-a]pyridine-2-carboxamide (40 mg, 0.097 mmol) in acetic acid (1 mL) was added platinum(iv) oxide (3 mg, 0.0096 mmol, 0.10 equiv). The reaction mixture stirred under a balloon of hydrogen gas for 72 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7,8-tetra hydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (10 mg, 25%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (m, 1H), 7.55-7.47 (m, 1H), 7.37-7.20 (m, 3H), 4.83 (dtd, J=11.2, 7.9, 3.1 Hz, 1H), 4.57 (ddd, J=17.1, 11.5, 9.8 Hz, 1H), 4.42 (dd, J=9.9, 7.7 Hz, 1H), 4.14 (dt, J=9.0, 4.3 Hz, 1H), 3.42-3.23 (m, 3H), 2.94-2.72 (m, 2H), 2.26 (ms, 1H), 2.00 (m, 2H), 1.90-1.57 (m, 6H), 1.32-1.21 (m, 1H), 1.11 (m, 5H). LC-MS R_(T)=5.60 min, m/z=424.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.60 min, ESI+ found [M+H]=424.2.

Example 378

(S)-5-ethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)-5-ethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo [1,5-a]pyridine-2-carboxamide was prepared corresponding from (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one, and 5-ethyl-2-iodo-[1,2,4]triazolo[1,5-a]pyridine according to Method GZ10. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step (35 mg, 26% yield) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (d, J=7.9 Hz, 1H), 7.86-7.71 (m, 2H), 7.53 (dd, J=7.5, 2.0 Hz, 1H), 7.39-7.17 (m, 4H), 4.91 (dt, J=11.5, 7.8 Hz, 1H), 4.64 (dd, J=11.5, 9.9 Hz, 1H), 4.49 (dd, J=9.9, 7.7 Hz, 1H), 3.34 (s, 3H), 3.32-3.12 (m, 2H), 1.36 (t, J=7.5 Hz, 3H). LC-MS R_(T)=4.57 min, m/z=366.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.57 min, ESI+ found [M+H]=366.1

Example 379

5-ethyl-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

5-ethyl-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6, 7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-5-ethyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2 affording final product (20 mg, 40%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (dd, J=10.8, 7.9 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 6.34 (d, J=2.0 Hz, 1H), 4.42-4.12 (m, 3H), 3.25 (d, J=1.9 Hz, 3H), 2.94-2.74 (m, 2H), 2.67-2.52 (m, 1H), 2.37 (dt, J=13.3, 8.2 Hz, 1H), 2.20-1.91 (m, 3H), 1.87-1.65 (m, 4H), 1.24 (s, 2H), 0.91 (t, J=7.4 Hz, 3H). LC-MS R_(T)=3.50 min, m/z=358.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.50 min, ESI+ found [M+H]=358.2

Example 380

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford final product (23 mg, 28%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (m, 1H), 7.48 (s, 1H), 7.40-7.26 (m, 3H), 7.09-7.02 (m, 2H), 6.33 (t, J=1.8 Hz, 1H), 5.57 (t, J=5.8 Hz, 1H), 4.26 (m, 3H), 3.23 (s, 3H), 3.11-2.87 (m, 2H), 2.57 (ddt, J=12.5, 8.2, 4.3 Hz, 1H), 2.37 (tq, J=11.8, 5.6 Hz, 2H), 2.05 (ddd, J=14.6, 7.5, 4.8 Hz, 1H), 1.86 (p, J=6.4 Hz, 2H). LC-MS R_(T)=3.95 min, m/z=406.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.95 min, ESI+ found [M+H]=406.2

Example 381

5-cyclohexyl-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

5-cyclohexyl-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ3. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) to afford final product (6.1 mg, 97%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55-8.35 (m, 1H), 7.50 (d, J=1.9 Hz, 1H), 6.35 (d, J=2.2 Hz, 1H), 4.41-4.31 (m, 1H), 4.26-4.10 (m, 2H), 3.45 (s, 3H), 2.94-2.84 (m, 1H), 2.00 (m, 2H), 1.76 (t, J=6.2 Hz, 2H), 1.68 (s, 10H), 1.43 (m, 2H), 1.24 (s, 4H), 1.12 (m, 4H). LC-MS R_(T)=4.71 min, m/z=412.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.71 min, ESI+ found [M+H]=412.2

Example 382

(S)-5-(2,5-difluorophenyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)-5-(2,5-difluorophenyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one, and 5-(2,5-difluorophenyl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine according to Method GZ1. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 59 mg, 48%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (d, J=7.7 Hz, 1H), 8.05 (dd, J=9.0, 1.2 Hz, 1H), 7.90 (dd, J=9.0, 7.1 Hz, 1H), 7.71 (tt, J=6.1, 2.1 Hz, 1H), 7.59-7.47 (m, 4H), 6.35 (d, J=2.0 Hz, 1H), 4.44-4.29 (m, 2H), 4.21 (ddd, J=14.4, 12.6, 6.6 Hz, 1H), 3.26 (s, 3H), 2.76-2.57 (m, 1H), 2.42 (m, 1H). LC-MS R_(T)=4.26 min, m/z=438.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.26 min, ESI+ found [M+H]=438.1

Example 383

5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-5-ethyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo [1,5-a]pyridine-2-carboxamide according to Method GZ2 affording final product (11.5 mg, 44%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (t, J=7.5 Hz, 1H), 7.50 (dd, J=7.5, 1.9 Hz, 1H), 7.37-7.20 (m, 3H), 4.83 (dtd, J=11.5, 7.8, 2.0 Hz, 1H), 4.56 (dt, J=11.4, 9.7 Hz, 1H), 4.41 (ddd, J=9.5, 7.7, 1.3 Hz, 1H), 4.17 (d, J=8.5 Hz, 1H), 2.95-2.76 (m, 2H), 2.18-1.91 (m, 3H), 1.86-1.65 (m, 3H), 0.91 (td, J=7.5, 1.4 Hz, 3H). LC-MS R_(T)=4.52 min, m/z=370.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.52 min, ESI+ found [M+H]=370.2

Examples 384 and 385

(S)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (R)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The crude residue was further purified by chiral SFC (Chiralpak AD 157×21.2 mm, 5 um, 30% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (S)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (7.1 mg, 20%) and (R)—N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phen yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (7.5 mg, 21%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R,S configuration): SFC R_(T) (AD column, 20% methanol isocratic elution with Carbon Dioxide, 2.5 min method): 0.94 min, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=7.9 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.40-7.26 (m, 3H), 7.09-7.01 (m, 2H), 6.33 (d, J=2.0 Hz, 1H), 5.57 (t, J=5.8 Hz, 1H), 4.41-4.11 (m, 3H), 3.24 (s, 3H), 3.10-2.90 (m, 2H), 2.57 (ddd, J=12.9, 8.0, 5.0 Hz, 1H), 2.37 (tq, J=12.4, 5.9 Hz, 2H), 2.11-1.98 (m, 1H), 1.86 (p, J=6.3 Hz, 2H). LCMS R_(T)=4.00 min, m/z=406.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.00 min, ESI+ found [M+H]=406.2

Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T) (AD column, 20% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 1.28 min, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=7.9 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.41-7.26 (m, 3H), 7.05 (dd, J=7.0, 1.8 Hz, 2H), 6.33 (d, J=2.0 Hz, 1H), 5.57 (t, J=5.9 Hz, 1H), 4.41-4.11 (m, 3H), 3.23 (s, 3H), 3.00 (qt, J=17.2, 6.3 Hz, 2H), 2.56 (ddd, J=12.9, 8.0, 5.0 Hz, 1H), 2.43-2.32 (m, 2H), 2.11-1.98 (m, 1H), 1.87 (q, J=6.2 Hz, 2H). LCMS R_(T)=4.00 min, m/z=406.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.00 min, ESI+ found [M+H]=406.2

Example 386

(S)-5-(2-fluorophenyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)-5-(2-fluorophenyl)-N-(4-methyl-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one, and 5-(2-fluorophenyl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine according to Method GZ1. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 18.3 mg, 17%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=7.7 Hz, 1H), 8.07-7.85 (m, 2H), 7.80-7.62 (m, 2H), 7.52-7.32 (m, 4H), 6.35 (d, J=2.0 Hz, 1H), 4.44-4.28 (m, 2H), 4.21 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 3.26 (s, 3H), 2.65 (tt, J=12.9, 8.1 Hz, 1H), 2.41 (td, J=12.4, 6.4 Hz, 1H). LC-MS R_(T)=4.19 min, m/z=420.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.19 min, ESI+ found [M+H]=420.1

Example 387

5-(2-fluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

5-(2-fluorophenyl)-N—((S)-4-methyl-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-5-(2-fluorophenyl)-N-(4-methyl-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford final product (13.1 mg, 36%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55-8.43 (m, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.44-7.34 (m, 1H), 7.29-7.14 (m, 2H), 6.94 (td, J=7.7, 1.7 Hz, 1H), 6.33 (t, J=1.6 Hz, 1H), 5.74 (t, J=6.5 Hz, 1H), 4.41-4.11 (m, 3H), 3.43-3.21 (m, 4H), 3.07-2.92 (m, 2H), 2.57 (dtd, J=17.3, 8.8, 8.3, 4.4 Hz, 1H), 2.39 (tt, J=12.7, 6.0 Hz, 2H), 2.15-2.01 (m, 1H), 1.92 (p, J=6.2 Hz, 2H). LC-MS R_(T)=3.95 min, m/z=424.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.95 min, ESI+ found [M+H]=424.2

Example 388

5-(2,5-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

5-(2,5-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydr-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-5-(2,5-difluorophenyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford final product (8 mg, 20%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (dd, J=12.8, 7.8 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.37-7.19 (m, 2H), 6.93 (dt, J=8.6, 4.2 Hz, 1H), 6.33 (t, J=1.7 Hz, 1H), 5.75-5.66 (m, 1H), 4.41-4.11 (m, 3H), 3.35 (d, J=16.9 Hz, 1H), 3.24 (d, J=1.7 Hz, 3H), 3.08-2.87 (m, 2H), 2.57 (ddt, J=16.7, 8.6, 3.8 Hz, 1H), 2.38 (dt, J=12.3, 6.2 Hz, 2H), 2.09 (q, J=11.1, 10.3 Hz, 1H), 1.95 (d, J=7.9 Hz, 2H). LC-MS R_(T)=4.19 min, m/z=442.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.19 min, ESI+ found [M+H]=442.2

Example 389 Method GZ14

(S)-5-(furan-3-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-(furan-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 2.347 mmol), furan-3-boronic acid (394 mg, 2.520 mmol), tripotassium phosphate (1495 mg, 7.041 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (67 mg, 0.141 mmol) and X-Phos aminobiphenyl palladium chloride precatalyst (XPhos-Pd-G2) (52 mg, 0.0705 mmol) was added under nitrogen. The microwave vial was capped and heated to 85° C. for 45 minutes. The reaction mixture was cooled down, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, triturated with isopropyl acetate, filtered out the solid to afford 5-(furan-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (400 mg, 85%) as a tan solid. LC-MS R_(T)=1.61 min, m/z=201.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.61 min, ESI+ found [M+H]=201.1.

Step 2: 5-(furan-3-yl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-(furan-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (300 mg, 1.424 mmol) and p-toluene sulphonic acid (1.04 g, 5.467 mmol) in acetonitrile (10 mL) was added a solution of potassium iodide (780 mg, 4.698 mmol) and sodium nitrite (247 mg, 3.573 mmol) in water (2 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×100) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 5-(furan-3-yl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (248 mg, 56%) as a light yellow solid. LC-MS R_(T)=2.48 min, m/z=312.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 2.48 min, ESI+ found [M+H]=312.1.

Step 3: (S)-5-(furan-3-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Palladium(II) acetate (7 mg, 0.032 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.0482 mmol), 5-(furan-3-yl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.321 mmol), (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (116 mg, 0.643 mmol) were added to a screw-cap vial. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (3 mL), and triethylamine (0.30 mL, 2.090 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial, with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The residue was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford (S)-5-(furan-3-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide as tan solid (58 mg, 59% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (d, J=1.4 Hz, 1H), 9.11 (d, J=7.9 Hz, 1H), 7.97 (t, J=1.8 Hz, 1H), 7.94-7.77 (m, 3H), 7.52 (d, J=2.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 4.50-4.38 (m, 2H), 4.24 (ddd, J=14.4, 12.6, 6.6 Hz, 1H), 3.29 (s, 3H), 2.76-2.50 (m, 2H). LC-MS R_(T)=3.95 min, m/z=392.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.95 min, ESI+ found [M+H]=392.1

Example 390

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(tetra hydrofuran-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-5-(furan-3-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford final product (0.8 mg, 2.5%) as a white solid. LC-MS R_(T)=3.21 min, m/z=400.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.21 min, ESI+ found [M+H]=400.2

Example 391 Method GZ9

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-phenylbenzo[d]thiazole-2-carboxamide

Step 1: 7-phenylbenzo[d]thiazole-2-carboxylic acid

A mixture of 7-bromobenzo[d]thiazole-2-carboxylic acid (500 mg, 1.88 mmol), phenyl boronic acid (458 mg, 3.76 mmol), potassium phosphate (1195 mg, 5.64 mmol) in Water (0.6 mL) and 1,4-dioxane (2 mL) was degassed, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (70 mg, 0.094 mmol) was added under nitrogen. The vial was capped and heated to 85° C. for 3 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to afford 7-phenylbenzo[d]thiazole-2-carboxylic acid (469 mg, 98%) as a fluffy tan solid, which was used in the next step without further purification.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 2.06 min, ESI+ found [M+H]=255.9.

Step 2: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-phenylbenzo[d]thiazole-2-carboxamide

To a solution of (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (93 mg, 0.409 mmol) and 7-phenylbenzo[d]thiazole-2-carboxylic acid (63 mg, 0.272 mmol) in N,N-dimethylformamide (2 mL) was added HATU (135 mg, 0.343 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.936 mmol). The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude residue was purified directly by preparative RP-HPLC (40-80% acetonitrile in water+0.1% formic acid) affording(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-phenylbenzo[d]thiazole-2-carboxamide (77 mg, 58%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (d, J=8.0 Hz, 1H), 8.22 (dd, J=8.1, 1.0 Hz, 1H), 7.83-7.68 (m, 4H), 7.62-7.45 (m, 4H), 7.30 (m, 3H), 4.89 (m, 1H), 4.75 (m, 1H), 4.48 (m, 1H), 3.33 (s, 3H). LC-MS R_(T)=6.75 min, m/z=430.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 6.75 min, ESI+ found [M+H]=430.1

Example 392

(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-phenylbenzo[d]thiazole-2-carboxamide

(S)—N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-7-phenylbenzo[d]thiazole-2-carboxamide was prepared from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one and 7-phenylbenzo[d]thiazole-2-carboxylic acid according to Method GZ9. The crude residue was purified directly by preparative RP-HPLC (30-70% acetonitrile in water+0.1% formic acid) to afford final product (79 mg, 57%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (d, J=7.7 Hz, 1H), 8.21 (dd, J=8.3, 1.1 Hz, 1H), 7.83-7.67 (m, 4H), 7.62-7.45 (m, 4H), 6.36 (d, J=2.0 Hz, 1H), 4.47-4.17 (m, 3H), 3.27 (s, 3H), 2.65 (m, 2H). LC-MS R_(T)=5.70 min, m/z=418.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.70 min, ESI+ found [M+H]=418.1

Example 393

(S)-5-(1-methyl-1H-pyrazol-4-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol-[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)-5-(1-methyl-1H-pyrazol-4-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one, and 2-iodo-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine according to Method GZ14. The residue was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 49.3 mg, 39.5%. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J=7.8 Hz, 1H), 8.94 (s, 1H), 8.51 (s, 1H), 7.87-7.72 (m, 3H), 7.52 (d, J=2.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 4.49-4.36 (m, 2H), 4.24 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 4.00 (s, 3H), 3.29 (s, 3H), 2.76-2.61 (m, 1H), 2.58-2.44 (m, 1H). LC-MS R_(T)=3.49 min, m/z=406.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.49 min, ESI+ found [M+H]=406.2

Example 394 Method GZ13

(S)-5-(2,6-difluorophenyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-(2,6-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (100 mg, 0.469 mmol), 2,6-difluorophenylboronic acid (227 mg, 1.408 mmol), potassium fluoride (82 mg, 1.408 mmol) in tetrahydrofuran (6 mL) and water (0.6 mL) was degassed, followed by adding tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.0469 mmol), tri-tert-butylphosphine (1.0 mol/l) in toluene (0.09 mL, 0.094 mmol) under nitrogen. The vial was capped and heated in a microwave to 120° C. for 15 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to afford 5-(2,6-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (102 mg, 88%) as a tan solid, which was used in the next step without further purification. LC-MS R_(T)=1.60 min, m/z=247.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.60 min, ESI+ found [M+H]=247.0.

Step 2: 5-(2,6-difluorophenyl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-(2,6-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (326 mg, 1.324 mmol) and p-toluene sulphonic acid (967 mg, 5.084 mmol) in acetonitrile (10 mL) was added a solution of potassium iodide (725 mg, 4.369 mmol) and sodium nitrite (229 mg, 3.323 mmol) in water (2 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×100 mL) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% iPrOAc in heptane) affording 5-(2,6-difluorophenyl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (339 mg, 72%) as a light yellow solid. LC-MS R_(T)=2.20 min, m/z=357.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 2.20 min, ESI+ found [M+H]=357.9.

Step 3: (S)-5-(2,6-difluorophenyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Palladium(II) acetate (10 mg, 0.042 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0.063 mmol), 5-(2,6-difluorophenyl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (150 mg, 0.420 mmol), (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (76 mg, 0.420 mmol) were added to a screw-cap vial. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (8 mL), and triethylamine (0.38 mL, 2.73 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial, with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite and concentrated down to dryness. The crude residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) to afford (S)-5-(2,6-difluorophenyl)-N-(4-methyl-5-oxo-5, 6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide as tan solid (141 mg, 77% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J=7.7 Hz, 1H), 8.10 (dd, J=9.0, 1.2 Hz, 1H), 7.93 (dd, J=9.0, 7.1 Hz, 1H), 7.76 (tt, J=8.5, 6.6 Hz, 1H), 7.59 (dd, J=7.1, 1.2 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.39 (t, J=8.4 Hz, 2H), 6.35 (d, J=2.0 Hz, 1H), 4.44-4.14 (m, 3H), 3.26 (s, 3H), 2.64 (tt, J=12.9, 8.1 Hz, 1H), 2.50-2.35 (m, 1H). LC-MS R_(T)=4.29 min, m/z=438.2 (M+H)

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.29 min, ESI+ found [M+H]=438.2

Example 395

(S)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1, 5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one, and 5-(3,6-dihydro-2H-pyran-4-yl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine according to Method GZ14. The residue was purified by SFC (5-60% methanol+0.1% ammonium hydroxide elution with Carbon Dioxide, Column HSS C18, 150×30 mm) instead. Yield of final step: 2.5 mg, 1.0%. LC-MS R_(T)=3.61 min, m/z=408.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.61 min, ESI+ found [M+H]=408.2

Example 396

5-(2,6-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

5-(2,6-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-5-(2,6-difluorophenyl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford final product (26.2 mg, 23%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (dd, J=20.1, 7.8 Hz, 1H), 7.54-7.39 (m, 2H), 7.14 (t, J=9.2 Hz, 2H), 6.32 (t, J=1.9 Hz, 1H), 5.85-5.70 (m, 1H), 4.41-4.10 (m, 3H), 3.23 (d, J=1.9 Hz, 3H), 3.09-2.85 (m, 2H), 2.64-2.50 (m, 1H), 2.48-2.29 (m, 2H), 2.20-1.97 (m, 3H). LC-MS R_(T)=4.25 min, m/z=442.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.25 min, ESI+ found [M+H]=442.2

Example 397

5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)-5-(1-methyl-1H-pyrazol-4-yl)-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) to afford final product (23 mg, 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.52-8.38 (m, 1H), 7.65-7.59 (m, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.37 (s, 1H), 6.33 (d, J=2.0 Hz, 1H), 5.47 (t, J=5.8 Hz, 1H), 4.42-4.12 (m, 3H), 3.79 (s, 3H), 3.24 (d, J=2.8 Hz, 3H), 3.02-2.83 (m, 2H), 2.66-2.52 (m, 1H), 2.43-2.24 (m, 2H), 2.19-2.05 (m, 1H), 1.93 (m, 2H). LC-MS R_(T)=3.11 min, m/z=410.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.11 min, ESI+ found [M+H]=410.2

Example 398

(S)-5-(1-methyl-1H-pyrazol-4-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)-5-(1-methyl-1H-pyrazol-4-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one, and 2-iodo-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine according to Method GZ14. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 60.8 mg, 32.0%. ¹H NMR (400 MHz, DMSO-d₆) δ 9.01-8.90 (m, 2H), 8.53 (s, 1H), 7.88-7.73 (m, 3H), 7.55 (dd, J=7.7, 1.8 Hz, 1H), 7.40-7.21 (m, 3H), 4.96 (dt, J=11.5, 7.9 Hz, 1H), 4.73 (dd, J=11.6, 9.8 Hz, 1H), 4.51 (dd, J=9.9, 7.8 Hz, 1H), 4.00 (s, 3H), 3.35 (s, 3H). LC-MS R_(T)=4.29 min, m/z=418.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.29 min, ESI+ found [M+H]=418.2

Example 399

(S)-5-(furan-3-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2, 4]triazolo[1,5-a]pyridine-2-carboxamide

(S)-5-(furan-3-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (51.3 mg, 0.267 mmol), and 5-(furan-3-yl)-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (83.0 mg, 0.267 mmol), according to Method GZ14. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 3.3 mg, 3.0%. ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s, 1H), 9.07 (d, J=8.2 Hz, 1H), 7.99 (t, J=1.9 Hz, 1H), 7.95-7.81 (m, 3H), 7.59-7.52 (m, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.40-7.24 (m, 3H), 4.99 (dt, J=11.8, 7.9 Hz, 1H), 4.74 (t, J=10.7 Hz, 1H), 4.49 (dd, J=9.9, 7.8 Hz, 1H), 3.35 (s, 3H). LC-MS R_(T)=4.93 min, m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.93 min, ESI+ found [M+H]=404.1

Examples 400 and 401 Method GZ_chiral_1

(S)-5-(2,6-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (R)-5-(2,6-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

5-(2,6-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydr-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was further purified by chiral SFC (WhelkO-1; 156×21.2 mm, 5 um; 45% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (S)-5-(2,6-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (32.2 mg, 28%) and (R)-5-(2,6-difluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (21.2 mg, 18%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T) (Whelkol s,s, 50% methanol isocratic elution with Carbon Dioxide, 2.5 min method): 0.658 min, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=7.8 Hz, 1H), 7.54-7.41 (m, 2H), 7.14 (t, J=9.0 Hz, 2H), 6.33 (d, J=2.0 Hz, 1H), 5.81 (dd, J=9.3, 5.5 Hz, 1H), 4.41-4.10 (m, 3H), 3.23 (s, 3H), 3.09-2.86 (m, 2H), 2.56 (m, 1H), 2.49-2.32 (m, 3H), 2.21-1.94 (m, 3H).

LCMS R_(T)=4.22 min, m/z=442.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.22 min, ESI+ found [M+H]=442.2

Analytical data for the second eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T)(Whelkol s,s, 50% methanol isocratic elution, 2.5 min method): 1.397 min, 100% ee:

¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (d, J=7.9 Hz, 1H), 7.54-7.41 (m, 2H), 7.14 (t, J=9.2 Hz, 2H), 6.32 (d, J=2.0 Hz, 1H), 5.81 (dd, J=9.2, 5.4 Hz, 1H), 4.41-4.11 (m, 3H), 3.23 (s, 3H), 3.12-2.87 (m, 2H), 2.57 (m, 1H), 2.38 (m, 3H), 2.20-1.98 (m, 3H). LCMS R_(T)=4.23 min, m/z=442.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.23 min, ESI+ found [M+H]=442.2

Examples 402 and 403 Method GZ_chiral_2

(R)-5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)-5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was further purified by chiral SFC (Chiralcel OX; 155×21.2 mm, 5 um; 40% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)-5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (17.6 mg, 16%) (S)-5-ethyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (19.8 mg, 18%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T) (OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.763 min, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J=8.1 Hz, 1H), 7.51 (dd, J=7.6, 1.9 Hz, 1H), 7.38-7.20 (m, 3H), 4.82 (dt, J=11.5, 7.8 Hz, 1H), 4.60 (dd, J=11.6, 9.8 Hz, 1H), 4.40 (dd, J=9.8, 7.7 Hz, 1H), 4.18 (s, 1H), 3.31 (s, 3H), 2.85 (q, J=6.9, 6.0 Hz, 2H), 2.18-1.91 (m, 3H), 1.86-1.65 (m, 3H), 0.91 (t, J=7.4 Hz, 3H). LCMS R_(T)=4.70 min, m/z=370.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.70 min, ESI+ found [M+H]=370.1

Analytical data for the second eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.242 min, 98.9% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=8.1 Hz, 1H), 7.51 (dd, J=7.6, 1.9 Hz, 1H), 7.38-7.20 (m, 3H), 4.83 (dt, J=11.4, 7.8 Hz, 1H), 4.57 (dd, J=11.5, 9.9 Hz, 1H), 4.40 (dd, J=9.8, 7.7 Hz, 1H), 4.18 (dt, J=12.0, 5.2 Hz, 1H), 3.34 (s, 3H), 2.92-2.79 (m, 2H), 2.18-2.02 (m, 2H), 1.98 (q, J=6.9 Hz, 1H), 1.86-1.66 (m, 3H), 0.90 (t, J=7.5 Hz, 3H). LCMS R_(T)=4.72 min, m/z=370.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.72 min, ESI+ found [M+H]=370.1

Example 404 Method GZ_chiral_3

(R)-5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[11,5-a]pyridine-2-carboxamide

5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was purified by chiral SFC (Chiralpak AD; 153×21.2 mm, 5 um; 35% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)-5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1, 5-a][1,3]diazepin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (5.2 mg, 4.6%) as white solids:

Analytical data: arbitrarily assigned (R, S configuration): SFC R_(T) (AD, 30% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.565 min, 97.8% purity, 95.5% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J=1.9 Hz, 1H), 7.38 (s, 1H), 6.35 (d, J=2.0 Hz, 1H), 5.47 (t, J=5.8 Hz, 1H), 4.42-4.12 (m, 3H), 3.79 (s, 3H), 3.24 (s, 3H), 2.93 (td, J=6.3, 3.2 Hz, 2H), 2.43-2.24 (m, 1H), 2.18-2.05 (m, 1H), 2.01-1.82 (m, 2H). LCMS R_(T)=3.16 min, m/z=410.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.16 min, ESI+ found [M+H]=410.2

Example 405 Method GZ4

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-(3,6-dihydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (600 mg, 2.82 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (915 mg, 4.22 mmol), tripotassium phosphate (1793 mg, 8.45 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (80 mg, 0.17 mmol) and X-Phos aminobiphenyl palladium chloride precatalyst, XPhos-Pd-G2 (80 mg, 0.08 mmol) was added under nitrogen. The microwave vial was capped and heated to 85° C. for 45 minutes. The reaction mixture was cooled down, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, triturated with isopropyl acetate, filtered out the solid to afford 5-(3,6-dihydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (502 mg, 83%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (dd, J=8.7, 7.4 Hz, 1H), 7.30 (dd, J=8.7, 1.3 Hz, 1H), 7.18 (tt, J=2.9, 1.5 Hz, 1H), 6.86 (dd, J=7.4, 1.3 Hz, 1H), 6.00 (s, 2H), 4.32 (q, J=2.8 Hz, 2H), 3.85 (t, J=5.4 Hz, 2H), 2.62 (dddd, J=6.6, 5.2, 3.3, 1.9 Hz, 2H). LCMS R_(T)=1.08 min, m/z=217.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.08 min, ESI+ found [M+H]=217.2.

Step 2: 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 5-(3,6-dihydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (870 mg, 4.02 mmol) in ethanol (15 mL), added acetic acid (15 mL), then added platinum(iv) oxide (45 mg, 0.20 mmol). The reaction mixture stirred under a balloon of hydrogen gas for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo affording 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (755 mg, 86%) as an off white solid. LC-MS R_(T)=1.15 min, m/z=219.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.15 min, ESI+ found [M+H]=219.1

Step 3: 2-iodo-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (750 mg, 3.44 mmol) and p-toluene sulphonic acid (2.51 g, 13.2 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (1.88 g, 11.34 mmol) and sodium nitrite (595 mg, 8.62 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×100) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% iPrOAc in heptane) affording 2-iodo-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (645 mg, 57%) as a light yellow solid. LC-MS R_(T)=1.76 min, m/z=330.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.76 min, ESI+ found [M+H]=330.0.

Step 4: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Palladium(II) acetate (13.6 mg, 0.061 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52.7 mg, 0.091 mmol), 2-iodo-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.607 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (125.5 mg, 0.668 mmol) were added to a screw-cap vial. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (10 mL), and triethylamine (0.55 mL, 3.95 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial, with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 16 h. The crude residue was dissolved in isopropyl acetate, and filtered through Celite. The crude residue was purified by flash column chromatography (silica gel, 0% to 100% isopropyl acetate in heptane) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (230 mg, 90% Yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J=7.9 Hz, 1H), 7.88-7.74 (m, 2H), 7.53 (dd, J=7.6, 1.9 Hz, 1H), 7.46-7.13 (m, 5H), 4.91 (dt, J=11.4, 7.8 Hz, 1H), 4.64 (dd, J=11.5, 9.9 Hz, 1H), 4.49 (dd, J=9.9, 7.7 Hz, 1H), 4.05-3.96 (m, 2H), 3.73 (tt, J=11.9, 3.6 Hz, 1H), 3.57 (td, J=11.8, 2.0 Hz, 2H), 3.30 (s, 3H), 2.05-1.96 (m, 2H), 1.89-1.72 (m, 2H). LCMS R_(T)=4.37 min, m/z=422.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.37 min, ESI+ found [M+H]=422.1.

Example 406 Method GZ11

(S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A suspension of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (700 mg, 3.29 mmol) in dioxane (12 mL) was degassed, cooled to ice bath, added 1,3-bis(diphenylphosphino)propane nickel (II) chloride (178 mg, 0.329 mmol) under nitrogen, followed by diisopropyl zinc (1M solution in toluene) via syringe over 10 mins. Removed the ice bath, heated up to 95° C. for overnight. The reaction mixture was poured into isopropyl alcohol, and concentrated to dryness in vacuo. The residue was diluted with saturated Ammonium chloride (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to afford 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (424 mg, 73%) as a tan solid which was used in the next step without further purification. LC-MS R_(T)=0.90 min, m/z=177.2 (M+H)+.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.90 min, ESI+ found [M+H]=177.2.

Step 2: 2-iodo-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (800 mg, 4.54 mmol) and p-toluene sulphonic acid (3.32 g, 17.43 mmol) in acetonitrile (40 mL) was added a solution of potassium iodide (2.49 g, 14.98 mmol) and sodium nitrite (786 mg, 11.40 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×100 mL) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% iPrOAc in heptane) affording 2-iodo-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine (534 mg, 41%) as a light yellow solid. LC-MS R_(T)=1.38 min, m/z=288.0 (M+H).

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.38 min, ESI+ found [M+H]=288.0.

Step 3: (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Palladium(II) acetate (16 mg, 0.069 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (61 mg, 0.104 mmol), 2-iodo-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.697 mmol), (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (147 mg, 0.766 mmol) were added to a screw-cap vial. Nitrogen was then purged through the reaction vial for 15 min. The solids were dissolved in toluene (10 mL), and triethylamine (0.63 mL, 4.53 mmol) was added. The reaction flask was purged with a balloon for carbon monoxide for 5 minutes. The vial, with the balloon of carbon monoxide, was placed in a 80° C. heating block and was allowed to stir for 16 h. The reaction mixture was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) to afford (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide as tan solid (152.8 mg, 58.0%) which was confirmed by ¹H NMR as 64% purity. ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (d, J=3.3 Hz, 1H), 7.85-7.79 (m, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.38-7.30 (m, 3H), 7.23-7.21 (s, 1H), 4.91 (m, 1H), 4.64 (m, 1H), 4.49 (m, 1H), 3.76 (p, J=6.8 Hz, 1H), 3.33 (s, 3H), 1.38 (dd, J=6.9, 0.9 Hz, 6H).

LC-MS R_(T)=5.13 min, m/z=380.1 (M+H)⁺. LC-MS R_(T)=5.13 min, m/z=380.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.13 min, ESI+ found [M+H]=380.1

Examples 407 and 411

(R)-5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)-5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was purified by chiral SFC (Chiralpak AD; 153×21.2 mm, 5 um; 35% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)-5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (5.0 mg, 8.25%) as white solids, and (S)-5-(1-methyl-1H-pyrazol-4-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (5.0 mg, 8.25%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (AD, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.600 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.49 (dd, J=7.6, 2.0 Hz, 1H), 7.39-7.19 (m, 4H), 5.47 (t, J=5.8 Hz, 1H), 4.81 (dt, J=11.4, 7.7 Hz, 1H), 4.55 (dd, J=11.5, 9.9 Hz, 1H), 4.39 (dd, J=9.9, 7.7 Hz, 1H), 3.78 (s, 3H), 3.31 (s, 3H), 2.93 (td, J=6.4, 2.6 Hz, 2H), 2.29 (ddd, J=8.6, 5.2, 3.3 Hz, 1H), 2.12 (dtd, J=14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03-1.83 (m, 2H). LCMS R_(T)=3.91 min, m/z=422.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.91 min, ESI+ found [M+H]=422.1

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T)(AD, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.978 min, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.49 (dd, J=7.6, 2.0 Hz, 1H), 7.39-7.19 (m, 4H), 5.47 (t, J=5.8 Hz, 1H), 4.81 (dt, J=11.4, 7.7 Hz, 1H), 4.55 (dd, J=11.5, 9.9 Hz, 1H), 4.39 (dd, J=9.9, 7.7 Hz, 1H), 3.78 (s, 3H), 3.31 (s, 3H), 2.93 (td, J=6.4, 2.6 Hz, 2H), 2.29 (ddd, J=8.6, 5.2, 3.3 Hz, 1H), 2.12 (dtd, J=14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03-1.83 (m, 2H). LCMS R_(T)=3.89 min, m/z=422.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.89 min, ESI+ found [M+H]=422.1

Example 408

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by SFC (Whelkol s,s, 50% methanol isocratic elution with Carbon Dioxide) to afford final product (58.7 mg, 18.3%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J=14.1, 8.0 Hz, 1H), 7.50 (dd, J=7.5, 2.0 Hz, 1H), 7.37-7.20 (m, 3H), 4.89-4.77 (m, 1H), 4.57 (ddd, J=16.0, 11.5, 9.9 Hz, 1H), 4.41 (dd, J=9.9, 7.7 Hz, 1H), 4.19 (dt, J=9.1, 4.8 Hz, 1H), 3.94-3.79 (m, 2H), 3.42-3.17 (m, 4H), 2.84 (dtt, J=21.9, 13.8, 5.0 Hz, 2H), 2.45 (m, 1H), 2.02 (dh, J=12.7, 7.2 Hz, 2H), 1.93-1.79 (m, 1H), 1.80-1.68 (m, 1H), 1.56 (d, J=13.4 Hz, 1H), 1.40 (dqd, J=16.1, 12.5, 4.2 Hz, 2H), 1.10 (d, J=13.3 Hz, 1H). LC-MS R_(T)=4.20 min, m/z=426.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.20 min, ESI+ found [M+H]=426.2

Examples 409 and 410

(R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was further purified by chiral SFC (WhelkO-1; 154×21.2 mm, 5 um; 50% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (41.9 mg, 13.0%) and (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (58.7 mg, 18.3%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (Whelkol s,s, 50% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.852 min, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J=14.1, 8.0 Hz, 1H), 7.50 (dd, J=7.5, 2.0 Hz, 1H), 7.37-7.20 (m, 3H), 4.89-4.77 (m, 1H), 4.57 (ddd, J=16.0, 11.5, 9.9 Hz, 1H), 4.41 (dd, J=9.9, 7.7 Hz, 1H), 4.19 (dt, J=9.1, 4.8 Hz, 1H), 3.94-3.79 (m, 2H), 3.42-3.17 (m, 4H), 2.84 (dtt, J=21.9, 13.8, 5.0 Hz, 2H), 2.45 (m, 1H), 2.02 (dh, J=12.7, 7.2 Hz, 2H), 1.93-1.79 (m, 1H), 1.80-1.68 (m, 1H), 1.56 (d, J=13.4 Hz, 1H), 1.40 (dqd, J=16.1, 12.5, 4.2 Hz, 2H), 1.10 (d, J=13.3 Hz, 1H). LCMS R_(T)=4.18 min, m/z=426.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.18 min, ESI+ found [M+H]=426.2

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T)(Whelkol s,s, 50% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.165 min, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J=14.1, 8.0 Hz, 1H), 7.50 (dd, J=7.5, 2.0 Hz, 1H), 7.37-7.20 (m, 3H), 4.89-4.77 (m, 1H), 4.57 (ddd, J=16.0, 11.5, 9.9 Hz, 1H), 4.41 (dd, J=9.9, 7.7 Hz, 1H), 4.19 (dt, J=9.1, 4.8 Hz, 1H), 3.94-3.79 (m, 2H), 3.42-3.17 (m, 4H), 2.84 (dtt, J=21.9, 13.8, 5.0 Hz, 2H), 2.45 (m, 1H), 2.02 (dh, J=12.7, 7.2 Hz, 2H), 1.93-1.79 (m, 1H), 1.80-1.68 (m, 1H), 1.56 (d, J=13.4 Hz, 1H), 1.40 (dqd, J=16.1, 12.5, 4.2 Hz, 2H), 1.10 (d, J=13.3 Hz, 1H). LCMS R_(T)=4.20 min, m/z=426.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.20 min, ESI+ found [M+H]=426.2

Example 412 Method GZ5

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 6-(trifluoromethyl)pyridin-2-amine (960 mg, 5.92 mmol) in dioxane (40 mL) was added ethoxycarbonyl isothiocyanate (0.77 mL, 6.52 mmol). The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was used for the next step without purification as ethyl N-[[6-(trifluoromethyl)-2-pyridyl]carbamothioyl]carbamate.

To a solution of hydroxylamine hydrochloride (960 mg, 5.92 mmol), N,N-diisopropylethylamine (0.77 mL, 6.52 mmol) in MeOH (8 mL) and EtOH (8 mL) was added a solution of crude ethyl N-[[6-(trifluoromethyl)-2-pyridyl]carbamothioyl]carbamate in MeOH (8 mL) and EtOH (8 mL). The reaction mixture was stirred at room temperature for 1 hour, heated to 60° C. for 18 hours till reaction complete. The reaction mixture was cooled down, the solvents were evaporated. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, triturated with isopropyl acetate, filtered out the solid to afford 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1066 mg, 89%) as a white solid.

LC-MS R_(T)=1.24 min, m/z=203.1 (M+H)⁺

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.24 min, ESI+ found [M+H]=203.1.

Step 2: 2-iodo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1066 mg, 5.06 mmol) and p-toluene sulphonic acid (3.70 g, 19.44 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (2.77 g, 16.71 mmol) and sodium nitrite (877 mg, 12.71 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% iPrOAc in heptane) affording 2-iodo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (929 mg, 58.6%) as a light yellow solid. LC-MS R_(T)=1.93 min, m/z=313.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.93 min, ESI+ found [M+H]=313.9.

Step 3: methyl 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a solution of 2-iodo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.798 mmol) in MeOH (15 mL)) in an Easy Max autoclave was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (60 mg, 0.08 mmol), trimethylamine (1.11 mL, 7.98 mmol). The autoclave was sealed, purged with CO twice, and pressured at 120 psi. The reaction mixture was stirred vigorously and heated at 80° C. for 15 h, concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording methyl 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (179 mg, 91.4%) as an off white solid. LC-MS R_(T)=1.10 min, m/z=246.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.10 min, ESI+ found [M+H]=246.0.

Step 4: 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

To a solution of methyl 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (64 mg, 0.261 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL) was added lithiumhydroxide (1 mol/L) in water (1 mL, 1.0 mmol). The reaction mixture was stirred at RT for 1 h. After this time, the mixture was concentrated to dryness in vacuo. The residue was diluted with water (2 mL) and then adjusted to pH=1 by addition of 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (60 mg, 99% yield) as a white solid used in the next step without further purification. LCMS R_(T)=0.88 min, m/z=232.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.88 min, ESI+ found [M+H]=232.2.

Step 5: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (93 mg, 0.409 mmol) and 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (63 mg, 0.272 mmol) in N,N-dimethylformamide (1.5 mL) was added HATU (120.9 mg, 0.327 mmol), and N,N-diisopropylethylamine (0.14 mL, 0.818 mmol. The reaction mixture was stirred overnight at RT, then was purified directly by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) affording (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1, 2,4]triazolo[1,5-a]pyridine-2-carboxamide (65.5 mg, 58%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J=7.8 Hz, 1H), 8.30 (dd, J=8.3, 2.0 Hz, 1H), 8.00-7.89 (m, 2H), 7.53 (dd, J=7.6, 2.0 Hz, 1H), 7.31 (dddd, J=21.7, 14.5, 7.4, 2.0 Hz, 3H), 4.92 (dt, J=11.4, 7.8 Hz, 1H), 4.66 (dd, J=11.6, 9.9 Hz, 1H), 4.49 (dd, J=9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LC-MS R_(T)=4.90 min, m/z=406.0 (M+H).

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.90 min, ESI+ found [M+H]=406.0

Examples 413-416

(R)-5-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)-5-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]methyl-4-oxo-1,2,4]oxazepin-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Mixture of 64% (S)-5-isopropyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and 36% (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was reduced according to Method GZ2. The crude residue was further purified by chiral SFC (Chiralpak ID; 150×21.2 mm, 5 um; 35% methanol isocratic elution with Carbon Dioxide) affording four isomers (structural isomers were assigned based on 1H NMR; diastereomers were arbitrarily assigned):

(R)-5-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (26 mg, 23%) as a white solid. (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (16.1 mg, 14%) as a white solid. (S)-5-isopropyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (22.6 mg, 19.8%) as a white solid. (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (12.7 mg, 10.5%) as a white solid.

Analytical data for the first eluting disomer (arbitrarily assigned R, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.655 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.49 (dd, J=7.6, 2.0 Hz, 1H), 7.39-7.19 (m, 4H), 5.47 (t, J=5.8 Hz, 1H), 4.81 (dt, J=11.4, 7.7 Hz, 1H), 4.55 (dd, J=11.5, 9.9 Hz, 1H), 4.39 (dd, J=9.9, 7.7 Hz, 1H), 3.78 (s, 3H), 3.31 (s, 3H), 2.93 (td, J=6.4, 2.6 Hz, 2H), 2.29 (ddd, J=8.6, 5.2, 3.3 Hz, 1H), 2.12 (dtd, J=14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03-1.83 (m, 2H). LCMS R_(T)=5.026 min, m/z=384.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.026 min, ESI+ found [M+H]=384.2

Analytical data for the second eluting isomer (arbitrarily assigned S, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.823 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J=8.0 Hz, 1H), 7.50 (dd, J=7.5, 2.0 Hz, 1H), 7.37-7.20 (m, 3H), 4.83 (dt, J=11.4, 7.8 Hz, 1H), 4.58 (dd, J=11.5, 9.8 Hz, 1H), 4.41 (dd, J=9.9, 7.7 Hz, 1H), 4.24 (d, J=13.1 Hz, 1H), 3.31 (s, 3H), 2.84 (q, J=6.1, 5.5 Hz, 2H), 2.19-1.91 (m, 3H), 1.85-1.57 (m, 3H), 1.48-1.29 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). LCMS R_(T)=5.12 min, m/z=384.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.12 min, ESI+ found [M+H]=384.2

Analytical data for the third eluting isomer (arbitrarily assigned S, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.391 min, 98.8% purity, 97.7% ee:: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.49 (dd, J=7.6, 2.0 Hz, 1H), 7.39-7.19 (m, 4H), 5.47 (t, J=5.8 Hz, 1H), 4.81 (dt, J=11.4, 7.7 Hz, 1H), 4.55 (dd, J=11.5, 9.9 Hz, 1H), 4.39 (dd, J=9.9, 7.7 Hz, 1H), 3.78 (s, 3H), 3.31 (s, 3H), 2.93 (td, J=6.4, 2.6 Hz, 2H), 2.29 (ddd, J=8.6, 5.2, 3.3 Hz, 1H), 2.12 (dtd, J=14.0, 7.5, 6.6, 3.0 Hz, 1H), 2.03-1.83 (m, 2H). LCMS R_(T)=5.03 min, m/z=384.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.03 min, ESI+ found [M+H]=384.2

Analytical data for the fourth eluting isomer (arbitrarily assigned R, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.475 min, 100% purity, 100% ee:: ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J=8.0 Hz, 1H), 7.50 (dd, J=7.5, 2.0 Hz, 1H), 7.37-7.20 (m, 3H), 4.83 (dt, J=11.4, 7.8 Hz, 1H), 4.58 (dd, J=11.5, 9.8 Hz, 1H), 4.41 (dd, J=9.9, 7.7 Hz, 1H), 4.24 (d, J=13.1 Hz, 1H), 3.31 (s, 3H), 2.84 (q, J=6.1, 5.5 Hz, 2H), 2.19-1.91 (m, 3H), 1.85-1.57 (m, 3H), 1.48-1.29 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). LCMS R_(T)=5.14 min, m/z=384.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.14 min, ESI+ found [M+H]=384.2

Example 417

(S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-3-amino-6, 8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, and 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid according to Method GZ5. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 123 mg, 78.0%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.88 (d, J=7.6 Hz, 1H), 8.31 (dd, J=8.3, 1.9 Hz, 1H), 8.01-7.90 (m, 2H), 7.25 (ddd, J=10.4, 9.1, 2.9 Hz, 1H), 7.06 (dt, J=9.3, 2.3 Hz, 1H), 5.00 (dt, J=10.9, 7.3 Hz, 1H), 4.72 (t, J=10.6 Hz, 1H), 4.60 (dd, J=10.2, 7.1 Hz, 1H). LC-MS R_(T)=4.72 min, m/z=428 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.72 min, ESI+ found [M+H]=428

Example 418

(S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-3-amino-7,9-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one, and 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid according to Method GZ5. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 80.9 mg, 51.7%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 8.72 (d, J=7.4 Hz, 1H), 8.30 (dd, J=8.2, 2.1 Hz, 1H), 8.00-7.89 (m, 2H), 7.29 (ddd, J=10.0, 8.9, 2.8 Hz, 1H), 7.21-7.13 (m, 1H), 4.43 (dt, J=11.5, 7.8 Hz, 1H), 3.37-3.22 (m, 3H), 2.87-2.74 (m, 2H), 2.39-2.25 (m, 1H). LC-MS R_(T)=4.69 min, m/z=426 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.69 min, ESI+ found [M+H]=426

Example 419

(S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-3-amino-6-fluoro-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, and 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid according to Method GZ5. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 86.2 mg, 55%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.86 (d, J=7.7 Hz, 1H), 8.31 (dd, J=8.3, 1.9 Hz, 1H), 8.01-7.90 (m, 2H), 7.00 (dd, J=10.7, 1.8 Hz, 1H), 6.92 (s, 1H), 4.94 (dt, J=11.0, 7.4 Hz, 1H), 4.67 (t, J=10.7 Hz, 1H), 4.54 (dd, J=10.2, 7.3 Hz, 1H), 2.31 (s, 3H). LC-MS R_(T)=4.98 min, m/z=424.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.98 min, ESI+ found [M+H]=424.1

Example 420 Method GZ12

(S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A suspension of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (700 mg, 3.29 mmol) in dioxane (12 mL) was degassed, cooled to ice bath, added 1,3-bis(diphenylphosphino)propane nickel (II) chloride (178 mg, 0.329 mmol) under nitrogen, followed by diisopropyl zinc (1M solution in toluene) via syringe over 10 mins. Removed the ice bath, heated up to 95° C. for overnight. The reaction mixture was poured into isopropyl alcohol, and concentrated to dryness in vacuo. The residue was diluted with saturated Ammonium chloride (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to afford 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (424 mg, 73%) as a tan solid, which was used in the next step without further purification. LCMS R_(T)=0.90 min, m/z=177.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.90 min, ESI+ found [M+H]=177.2.

Step 2: 2-iodo-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (800 mg, 4.54 mmol) and p-toluene sulphonic acid (3.32 g, 17.43 mmol) in acetonitrile (40 mL) was added a solution of potassium iodide (2.49 g, 14.98 mmol) and sodium nitrite (786 mg, 11.40 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×100 mL) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording 2-iodo-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine (534 mg, 41%) as a light yellow solid. LCMS R_(T)=1.38 min, m/z=288.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.38 min, ESI+ found [M+H]=288.0.

Step 3: methyl 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a solution of 2-iodo-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine (1000 mg, 3.48 mmol) in MeOH (20 mL)) in an Easy Max autoclave was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (260 mg, 0.348 mmol), trimethylamine (4.85 mL, 34.83 mmol). The autoclave was sealed, purged with CO twice, and pressured at 120 psi. The reaction mixture was stirred vigorously and heated at 80° C. for 15 h, concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording methyl 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (710 mg, 93%) as an off white solid.

LCMS R_(T)=1.14 min, m/z=220.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.14 min, ESI+ found [M+H]=220.1.

Step 4: 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

To a solution of methyl 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (806 mg, 3.68 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added lithiumhydroxide (1 mol/L) in water (7 mL, 7.0 mmol). The reaction mixture was stirred at RT for 1 h. After this time, the mixture was concentrated to dryness in vacuo. The residue was diluted with water (2 mL) and then adjusted to pH=1 by addition of 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3×75 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (716 mg, 95% yield) as a white solid used in the next step without further purification. LCMS R_(T)=0.96 min, m/z=206.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.96 min, ESI+ found [M+H]=206.2.

Step 5: (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of (S)-3-amino-7,9-difluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (132 mg, 0.532 mmol) and 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (95 mg, 0.460 mmol) in N,N-dimethylformamide (1.5 mL) was added HATU (215 mg, 0.560 mmol), and N,N-diisopropylethylamine (0.24 mL, 1.39 mmol. The reaction mixture was stirred overnight at RT, then was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) to afford as tan solid (103.7 mg, 56%) as a mixture of 64% (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and 36% (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-propyl-[1,2,4]triazol o[1,5-a]pyridine-2-carboxamide. This final compound was observed as single peak by LC-MS, was confirmed by ¹H NMR which showed purity was 64%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 8.63 (dd, J=7.5, 3.0 Hz, 1H), 7.85-7.68 (m, 3H), 7.29 (ddd, J=10.2, 8.9, 2.8 Hz, 1H), 7.18 (ddt, J=11.0, 8.7, 1.9 Hz, 3H), 4.43 (dt, J=11.6, 7.7 Hz, 1H), 3.77 (h, J=6.8 Hz, 1H), 3.39-3.25 (m, 1H), 2.83 (dd, J=11.1, 5.5 Hz, 2H), 2.30 (ddt, J=12.4, 9.3, 4.0 Hz, 1H), 1.39 (d, J=6.9 Hz, 6H). LC-MS R_(T)=4.92 min, m/z=400.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.92 min, ESI+ found [M+H]=400.1

Example 421 Method GZ15

(S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 2.347 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (977 mg, 4.694 mmol), tripotassium phosphate (1541 mg, 7.041 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (67 mg, 0.141 mmol) and X-Phos aminobiphenyl palladium chloride precatalyst, XPhos-Pd-G2 (63 mg, 0.071 mmol) was added under nitrogen. The microwave vial was capped and heated to 85° C. for 45 minutes. The reaction mixture was cooled down, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, triturated with isopropyl acetate, filtered out the solid to afford 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (385 mg, 76.7%) as a brown solid. LC-MS R_(T)=1.10 min, m/z=215.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.10 min, ESI+ found [M+H]=215.0.

Step 2: 2-iodo-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1011 mg, 4.719 mmol) and p-toluene sulphonic acid (3.45 g, 18.122 mmol) in acetonitrile (30 mL) was added a solution of potassium iodide (2590 mg, 15.573 mmol) and sodium nitrite (817 mg, 11.845 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×150) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% iPrOAc in heptane) affording 2-iodo-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (800 mg, 52%) as a light yellow solid. LC-MS R_(T)=2.04 min, m/z=325.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 2.04 min, ESI+ found [M+H]=325.9.

Step 3: methyl 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a solution of 2-iodo-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (800 mg, 2.461 mmol) in MeOH (20 mL)) in an Easy Max autoclave was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (184 mg, 0.246 mmol), trimethylamine (3.43 mL, 24.607 mmol). The autoclave was sealed, purged with CO twice, and pressured at 120 psi. The reaction mixture was stirred vigorously and heated at 80° C. for 15 h, concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording methyl 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (574 mg, 91%) as a brown solid. LC-MS R_(T)=0.97 min, m/z=258.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.97 min, ESI+ found [M+H]=258.1.

Step 4: 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

To a solution of methyl 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (574 mg, 2.231 mmol) in tetrahydrofuran (12 mL) and methanol (3 mL) was added lithiumhydroxide (1 mol/L) in water (4 mL, 1.0 mmol). The reaction mixture was stirred at RT for 1 h. After this time, the mixture was concentrated to dryness in vacuo. The residue was diluted with water (15 mL) and then adjusted to pH=1 by addition of 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (381 mg, 70% yield) as a brown solid used in the next step without further purification. LCMS R_(T)=0.92 min, m/z=244.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.92 min, ESI+ found [M+H]=244.1.

Step 5: (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (95 mg, 0.378 mmol) and 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (80 mg, 0.329 mmol) in N,N-dimethylformamide (1.5 mL) was added HATU (153 mg, 0.395 mmol), and N,N-diisopropylethylamine (0.23 mL, 1.316 mmol. The reaction mixture was stirred overnight at RT, then was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide as tan solid (2 mg, 1.4% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 2H), 8.96-8.89 (m, 4H), 8.53 (s, 2H), 7.88-7.73 (m, 6H), 7.26 (ddd, J=10.3, 9.0, 2.9 Hz, 2H), 7.07 (dt, J=9.1, 2.2 Hz, 2H), 5.02 (dt, J=11.1, 7.5 Hz, 2H), 4.78 (t, J=10.7 Hz, 2H), 4.62 (dd, J=10.2, 7.2 Hz, 2H), 4.00 (s, 6H), 3.32-3.22 (m, 1H), 2.47 (s, 1H). LC-MS R_(T)=4.31 min, m/z=440.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.31 min, ESI+ found [M+H]=440.1

Example 422 Method GZ16

(S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 5-(3,6-dihydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (600 mg, 2.82 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (915 mg, 4.22 mmol), tripotassium phosphate (1793 mg, 8.45 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was degassed, then 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (80 mg, 0.17 mmol) and X-Phos aminobiphenyl palladium chloride precatalyst, XPhos-Pd-G2 (80 mg, 0.08 mmol) was added under nitrogen. The microwave vial was capped and heated to 85° C. for 45 minutes. The reaction mixture was cooled down, diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, triturated with isopropyl acetate, filtered out the solid to afford 5-(3,6-dihydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (502 mg, 83%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (dd, J=8.7, 7.4 Hz, 1H), 7.30 (dd, J=8.7, 1.3 Hz, 1H), 7.18 (tt, J=2.9, 1.5 Hz, 1H), 6.86 (dd, J=7.4, 1.3 Hz, 1H), 6.00 (s, 2H), 4.32 (q, J=2.8 Hz, 2H), 3.85 (t, J=5.4 Hz, 2H), 2.62 (dddd, J=6.6, 5.2, 3.3, 1.9 Hz, 2H). LCMS R_(T)=1.08 min, m/z=217.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.08 min, ESI+ found [M+H]=217.2.

Step 2: 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of 5-(3,6-dihydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (870 mg, 4.02 mmol) in ethanol (15 mL), added acetic acid (15 mL), then added platinum(iv) oxide (45 mg, 0.20 mmol). The reaction mixture stirred under a balloon of hydrogen gas for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with isopropyl acetate (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo affording 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (755 mg, 86%) as an off white solid. LC-MS R_(T)=1.15 min, m/z=219.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.15 min, ESI+ found [M+H]=219.1

Step 3: 2-iodo-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine

To a solution of 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (750 mg, 3.44 mmol) and p-toluene sulphonic acid (2.51 g, 13.2 mmol) in acetonitrile (45 mL) was added a solution of potassium iodide (1.88 g, 11.34 mmol) and sodium nitrite (595 mg, 8.62 mmol) in water (5 mL) at 24° C. After 18 h, isopropyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×100) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% iPrOAc in heptane) affording 2-iodo-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (645 mg, 57%) as a light yellow solid. LC-MS R_(T)=1.76 min, m/z=330.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 5 mins) retention time 1.76 min, ESI+ found [M+H]=330.0.

Step 3: methyl 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a solution of 2-iodo-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (144 mg, 0.438 mmol) in MeOH (15 mL)) in an Easy Max autoclave was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33 mg, 0.0438 mmol), trimethylamine (0.61 mL, 4.375 mmol). The autoclave was sealed, purged with CO twice, and pressured at 120 psi. The reaction mixture was stirred vigorously and heated at 80° C. for 15 h, concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording methyl 5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (79 mg, 79%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.9 Hz, 1H), 7.78 (dd, J=9.0, 7.1 Hz, 1H), 7.25 (d, J=7.1 Hz, 1H), 4.07-3.97 (m, 2H), 3.95 (d, J=1.3 Hz, 3H), 3.72 (tt, J=12.1, 3.7 Hz, 1H), 3.58 (t, J=11.6 Hz, 2H), 2.07-1.94 (m, 2H), 1.82 (qd, J=12.3, 4.3 Hz, 2H).

LC-MS R_(T)=1.10 min, m/z=262.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.10 min, ESI+ found [M+H]=262.2.

Step 4: 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

To a solution of methyl 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (143 mg, 0.547 mmol) in tetrahydrofuran (12 mL) and methanol (3 mL) was added lithiumhydroxide (1 mol/L) in water (3 mL, 3.010 mmol). The reaction mixture was stirred at RT for 1 h. After this time, the mixture was concentrated to dryness in vacuo. The residue was diluted with water (15 mL) and then adjusted to pH=1 by addition of 1 N hydrochloric acid. The solution was extracted with isopropyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo to afford 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (65 mg, 48% yield) as a tan solid used in the next step without further purification. LCMS R_(T)=0.72 min, m/z=248.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 0.72 min, ESI+ found [M+H]=248.1.

Step 5: (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

To a solution of (S)-3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (112 mg, 0.447 mmol) and 5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (85 mg, 0.343 mmol) in N,N-dimethylformamide (1.5 mL) was added HATU (160 mg, 0.412 mmol), and N,N-diisopropylethylamine (0.18 mL, 1.031 mmol. The reaction mixture was stirred overnight at RT, then was purified by preparative RP-HPLC (5-50% acetonitrile in water+0.1% formic acid) to afford (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide as a white solid (15.2 mg, 10.0%). ¹H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.81 (d, J=7.6 Hz, 1H), 7.88-7.74 (m, 2H), 7.30-7.20 (m, 2H), 7.06 (dt, J=9.3, 2.3 Hz, 1H), 4.99 (dt, J=11.0, 7.3 Hz, 1H), 4.71 (t, J=10.7 Hz, 1H), 4.59 (dd, J=10.2, 7.2 Hz, 1H), 4.06-3.97 (m, 2H), 3.74 (m, 1H), 3.58 (m, 2H), 2.10-1.96 (m, 2H), 1.82 (m, 2H). LC-MS R_(T)=4.44 min, m/z=444.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.44 min, ESI+ found [M+H]=444.1

Example 423

(S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-3-amino-6-fluoro-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, and 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid according to Method GZ12. The residue was purified by SFC (5-40% methanol elution with Carbon Dioxide, Column: Pyridyl Amide 150×30 mm) to afford (S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide which showed 64% purity by ¹H NMR, single peak for LC-MS. Yield of final step: 74 mg, 40%. ¹H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.76 (dd, J=7.8, 2.6 Hz, 1H), 7.86-7.70 (m, 2H), 7.21 (dt, J=6.9, 1.8 Hz, 1H), 7.00 (dd, J=10.8, 1.8 Hz, 1H), 6.91 (s, 1H), 4.94 (dt, J=11.2, 7.4 Hz, 1H), 4.65 (t, J=10.6 Hz, 1H), 4.54 (ddd, J=9.3, 7.4, 1.6 Hz, 1H), 3.77 (p, J=6.9 Hz, 1H), 2.31 (s, 3H), 1.39 (d, J=6.9 Hz, 6H).

LC-MS R_(T)=5.21 min, m/z=398.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.21 min, ESI+ found [M+H]=398.1

Example 424

(S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

(S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared corresponding from (S)-3-amino-6, 8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, and 5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid according to Method GZ12. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) to afford (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide which showed 64% purity by ¹H NMR, single peak for LC-MS. Yield of final step: 69.8 mg, 37.6%. ¹H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.78 (dd, J=7.6, 2.7 Hz, 1H), 7.86-7.70 (m, 2H), 7.30-7.17 (m, 2H), 7.06 (dt, J=9.4, 2.3 Hz, 1H), 5.05-4.93 (m, 1H), 4.71 (t, J=10.7 Hz, 1H), 4.59 (ddd, J=10.2, 7.1, 1.5 Hz, 1H), 3.77 (p, J=6.9 Hz, 1H), 3.38-3.23 (m, 1H), 1.39 (d, J=6.9 Hz, 6H). LC-MS R_(T)=5.01 min, m/z=402.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.01 min, ESI+ found [M+H]=402.1

Examples 425 and 426

(R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1, 2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was further purified by chiral SFC (Cellulose-1; 155×21.2 mm, 5 um; 20% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (15 mg, 13%) and (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (16.5 mg, 14.5%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (Cel-1, 15% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.989 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.9 Hz, 1H), 7.51 (dd, J=7.5, 1.9 Hz, 1H), 7.37-7.20 (m, 3H), 5.41 (h, J=6.8 Hz, 1H), 4.83 (dt, J=11.5, 7.8 Hz, 1H), 4.61 (dd, J=11.6, 9.8 Hz, 1H), 4.42 (dd, J=9.8, 7.7 Hz, 1H), 3.42-3.18 (m, 3H), 3.07-2.87 (m, 2H), 2.39-2.15 (m, 2H), 2.02-1.87 (m, 2H). LCMS R_(T)=4.760 min, m/z=410.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.760 min, ESI+ found [M+H]=410.1

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T)(Cel-1, 15% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.372 min, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.9 Hz, 1H), 7.51 (dd, J=7.5, 1.9 Hz, 1H), 7.37-7.20 (m, 3H), 5.41 (h, J=6.8 Hz, 1H), 4.83 (dt, J=11.5, 7.8 Hz, 1H), 4.61 (dd, J=11.6, 9.8 Hz, 1H), 4.42 (dd, J=9.8, 7.7 Hz, 1H), 3.42-3.18 (m, 3H), 3.07-2.87 (m, 2H), 2.39-2.15 (m, 2H), 2.02-1.87 (m, 2H). LCMS R_(T)=4.81 min, m/z=410.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.81 min, ESI+ found [M+H]=410.1

Examples 427 and 428

(R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The crude residue was further purified by chiral SFC (Chiralpak AD; 152×21.2 mm, 5 um; 30% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (27.2 mg, 32%) and (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (26.6 mg, 32.5%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.624 min, 98.5% purity, 97% ee: ¹H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.47 (d, J=7.7 Hz, 1H), 6.99 (dd, J=10.8, 1.8 Hz, 1H), 6.89 (s, 1H), 5.41 (h, J=6.8 Hz, 1H), 4.85 (dt, J=11.1, 7.4 Hz, 1H), 4.61 (t, J=10.7 Hz, 1H), 4.47 (dd, J=10.1, 7.2 Hz, 1H), 3.07-2.87 (m, 2H), 2.30 (m, 5H), 1.96 (h, J=6.7 Hz, 2H). LCMS R_(T)=4.44 min, m/z=428.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.44 min, ESI+ found [M+H]=428.1

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T)(AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.200 min, 100% ee: ¹H 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.47 (d, J=7.7 Hz, 1H), 6.99 (dd, J=10.8, 1.8 Hz, 1H), 6.89 (s, 1H), 5.41 (h, J=6.8 Hz, 1H), 4.85 (dt, J=11.1, 7.4 Hz, 1H), 4.61 (t, J=10.7 Hz, 1H), 4.47 (dd, J=10.1, 7.2 Hz, 1H), 3.07-2.87 (m, 2H), 2.30 (m, 5H), 1.96 (h, J=6.7 Hz, 2H). LCMS R_(T)=4.50 min, m/z=428.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.50 min, ESI+ found [M+H]=428.1

Examples 429 and 430

(R)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The crude residue was further purified by chiral SFC (Chiralpak AD; 151×21.2 mm, 5 um; 30% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (23.5 mg, 29.7%) and (S)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (20.6 mg, 26.0%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.568 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.33 (d, J=7.5 Hz, 1H), 7.27 (ddd, J=10.2, 8.9, 2.8 Hz, 1H), 7.18-7.10 (m, 1H), 5.40 (h, J=6.8 Hz, 1H), 4.34 (dt, J=11.5, 7.8 Hz, 1H), 3.06-2.71 (m, 4H), 2.50-2.15 (m, 4H), 1.94 (m, 2H). LCMS R_(T)=4.16 min, m/z=430.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.16 min, ESI+ found [M+H]=430.1

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T)(AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.873 min, 98.07% purity, 96.14% ee: ¹H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.33 (d, J=7.5 Hz, 1H), 7.27 (ddd, J=10.2, 8.9, 2.8 Hz, 1H), 7.18-7.10 (m, 1H), 5.40 (h, J=6.8 Hz, 1H), 4.34 (dt, J=11.5, 7.8 Hz, 1H), 3.06-2.71 (m, 4H), 2.50-2.15 (m, 4H), 1.94 (m, 2H). LCMS R_(T)=4.22 min, m/z=430.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.22 min, ESI+ found [M+H]=430.1

Examples 431 and 432

(R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The crude residue was further purified by chiral SFC (Chiralpak AD; 150×21.2 mm, 5 um; 30% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (19.8 mg, 17.9%) and (S)—N—((S)-6, 8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (21.0 mg, 20.2%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.535 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.50 (d, J=7.6 Hz, 1H), 7.23 (ddd, J=10.3, 9.0, 2.9 Hz, 1H), 7.03 (dt, J=9.4, 2.3 Hz, 1H), 5.42 (h, J=6.8 Hz, 1H), 4.90 (dt, J=11.1, 7.3 Hz, 1H), 4.67 (t, J=10.7 Hz, 1H), 4.53 (dd, J=10.1, 7.1 Hz, 1H), 3.07-2.87 (m, 2H), 2.40-2.16 (m, 2H), 1.96 (h, J=6.6 Hz, 2H). LCMS R_(T)=4.24 min, m/z=432.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.24 min, ESI+ found [M+H]=432.1

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T)(AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.849 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.50 (d, J=7.6 Hz, 1H), 7.23 (ddd, J=10.3, 9.0, 2.9 Hz, 1H), 7.03 (dt, J=9.4, 2.3 Hz, 1H), 5.42 (h, J=6.8 Hz, 1H), 4.90 (dt, J=11.1, 7.3 Hz, 1H), 4.67 (t, J=10.7 Hz, 1H), 4.53 (dd, J=10.1, 7.1 Hz, 1H), 3.07-2.87 (m, 2H), 2.40-2.16 (m, 2H), 1.96 (h, J=6.6 Hz, 2H). LCMS R_(T)=4.29 min, m/z=432.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.29 min, ESI+ found [M+H]=432.1.

Example 433

N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-H-benzo[b]azepin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was prepared from (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide according to Method GZ2. The residue was purified by preparative RP-HPLC (5-60% acetonitrile in water+0.1% formic acid) to afford final product (7.3 mg, 10.3%) as a white. ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.19 (dd, J=7.6, 4.1 Hz, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 7.26 (td, J=9.6, 2.8 Hz, 1H), 7.14 (dd, J=8.2, 2.7 Hz, 1H), 5.46 (t, J=5.8 Hz, 1H), 4.32 (dt, J=11.4, 7.8 Hz, 1H), 4.08 (q, J=5.3 Hz, 1H), 3.78 (s, 3H), 3.17 (d, J=5.3 Hz, 3H), 2.92 (dt, J=10.0, 5.4 Hz, 2H), 2.82-2.71 (m, 2H), 2.33-2.17 (m, 2H), 2.12 (m, 1H), 1.92 (dd, J=20.0, 10.3 Hz, 2H). LC-MS R_(T)=3.85 min, m/z=442.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.85 min, ESI+ found [M+H]=442.1

Examples 434-437

(R)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-isopropyl-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-propyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-H-benzo[b]azepin-3-yl)-5-isopropyl-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (R)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1-benzo[b]azepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Mixture of 64% (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and 36% (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-propyl-[1,2,4]triazol o[1,5-a]pyridine-2-carboxamide was reduced according to Method GZ2. The crude residue was further purified by chiral SFC was purified by chiral SFC (Chiralpak ID; 150×21.2 mm, 5 um; 30% methanol isocratic elution with Carbon Dioxide) affording four isomers (structural isomers were assigned based on 1H NMR; diastereomers were arbitrarily assigned):

(R)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-isopropyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (19.6 mg, 19.8%) as white solids (S)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (8.8 mg, 8.2%) as white solids (S)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-isopropyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (19 mg, 18.6%) as white solids (R)—N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (8.1 mg, 8.2%) as white solids.

Analytical data for the first eluting isomer (arbitrarily assigned R, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.719 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.27 (ddd, J=10.1, 8.9, 2.8 Hz, 1H), 7.19-7.10 (m, 1H), 4.34 (dt, J=11.5, 7.8 Hz, 1H), 4.15 (p, J=4.4 Hz, 1H), 2.95-2.85 (m, 1H), 2.72 (dtd, J=59.4, 7.0, 6.5, 4.0 Hz, 5H), 2.50-2.37 (m, 1H), 2.30-2.16 (m, 1H), 2.10-1.96 (m, 2H), 1.73 (ddd, J=10.7, 8.2, 5.2 Hz, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.68 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.72 min, m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.72 min, ESI+ found [M+H]=404.1

Analytical data for the second eluting isomer (arbitrarily assigned S, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.950 min, 99.6% purity, 99.2% ee: ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.27 (ddd, J=10.1, 8.9, 2.8 Hz, 1H), 7.18-7.10 (m, 1H), 4.34 (dt, J=11.5, 7.9 Hz, 1H), 4.21 (d, J=7.5 Hz, 1H), 2.93-2.71 (m, 4H), 2.50-2.36 (m, 1H), 2.30-1.91 (m, 4H), 1.86-1.57 (m, 3H), 1.38 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). LCMS R_(T)=4.85 min, m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.85 min, ESI+ found [M+H]=404.1

Analytical data for the third eluting isomer (arbitrarily assigned S, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.368 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.27 (ddd, J=10.1, 8.9, 2.8 Hz, 1H), 7.19-7.10 (m, 1H), 4.34 (dt, J=11.5, 7.8 Hz, 1H), 4.15 (p, J=4.4 Hz, 1H), 2.95-2.85 (m, 1H), 2.72 (dtd, J=59.4, 7.0, 6.5, 4.0 Hz, 5H), 2.50-2.37 (m, 1H), 2.30-2.16 (m, 1H), 2.10-1.96 (m, 2H), 1.73 (ddd, J=10.7, 8.2, 5.2 Hz, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.68 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.78 min, m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.78 min, ESI+ found [M+H]=404.1

Analytical data for the fourth eluting isomer (arbitrarily assigned R, S configuration): SFC R_(T)(OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.439 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.27 (ddd, J=10.1, 8.9, 2.8 Hz, 1H), 7.18-7.10 (m, 1H), 4.34 (dt, J=11.5, 7.9 Hz, 1H), 4.21 (d, J=7.5 Hz, 1H), 2.93-2.71 (m, 4H), 2.50-2.36 (m, 1H), 2.30-1.91 (m, 4H), 1.86-1.57 (m, 3H), 1.38 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). LCMS R_(T)=4.88 min, m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.88 min, ESI+ found [M+H]=404.1

Examples 438-441

(R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[1,4]oxazepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4][triazolo[1,5-a]pyridine-2-carboxamide

Mixture of 64% (S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[b[1,5][1,5-a]pyridine-2-carboxamide and 36(3.5 g, 5.0%) as white (S)—N-(6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was reduced according to Method GZ2. The crude residue was further purified by chiral SFC was purified by chiral SFC (Chiralpak TD; 150×21.2 mm, Sum; 35% methanol isocratic elution with Carbon Dioxide) affording four isomers (structural isomers were assigned based on 1H NMR; diastereomers arbitrarily assigned):

(R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (3.5 mg, 5.0%) as white solids (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1.6 mg, 2.1%) as white solids (S)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (4.1 mg, 5.8%) as white solids (R)—N—((S)-6-fluoro-8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1.8 mg, 2.4%) as white solids.

Analytical data for the first eluting isomer (arbitrarily assigned R, S configuration): SFC R_(T)(AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.874 min, 99.3% purity, 98.5% ee: ¹H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 7.03-6.94 (m, 1H), 6.89 (s, 1H), 4.84 (dt, J=11.1, 7.5 Hz, 1H), 4.59 (t, J=10.7 Hz, 1H), 4.46 (dd, J=10.1, 7.3 Hz, 1H), 4.16 (dt, J=8.6, 4.6 Hz, 1H), 2.96-2.85 (m, 1H), 2.79 (ddd, J=17.7, 9.9, 5.3 Hz, 1H), 2.72-2.59 (m, 1H), 2.30 (s, 3H), 2.07-1.98 (m, 2H), 1.73 (ddd, J=10.8, 8.5, 5.7 Hz, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.94 min, m/z=402.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.94 min, ESI+ found [M+H]=402.1

Analytical data for the second eluting isomer (arbitrarily assigned S, S configuration): SFC R_(T)(AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.019 min, 94.3% purity, 88.6% ee: LCMS R_(T)=5.05 min, m/z=402.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.05 min, ESI+ found [M+H]=402.1

Analytical data for the third eluting isomer (arbitrarily assigned S, S configuration): SFC R_(T)(AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.220 min, 98.3% purity, 96.6% ee: ¹H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 7.03-6.94 (m, 1H), 6.89 (s, 1H), 4.84 (dt, J=11.1, 7.5 Hz, 1H), 4.59 (t, J=10.7 Hz, 1H), 4.46 (dd, J=10.1, 7.3 Hz, 1H), 4.16 (dt, J=8.6, 4.6 Hz, 1H), 2.96-2.85 (m, 1H), 2.79 (ddd, J=17.7, 9.9, 5.3 Hz, 1H), 2.72-2.59 (m, 1H), 2.30 (s, 3H), 2.07-1.98 (m, 2H), 1.73 (ddd, J=10.8, 8.5, 5.7 Hz, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.91 min, m/z=402.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.91 min, ESI+ found [M+H]=402.1

Analytical data for the fourth eluting isomer (arbitrarily assigned R, S configuration): SFC R_(T)(AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.513 min, 95.8% purity, 91.6% ee: LCMS R_(T)=5.08 min, m/z=402.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.08 min, ESI+ found [M+H]=402.1.

Example 442

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

Utilizing 3-phenylpyrazin-2-amine to replace 6-(trifluoromethyl)pyridin-2-amine in step 1 of Method GZ5, follow the steps. (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazol o[1,5-a]pyrazine-2-carboxamide was prepared corresponding from (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, and 8-phenyl-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid according to Method GZ5. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 35.5 mg, 22.9%. ¹H NMR (400 MHz, DMSO-d6) δ 9.15-9.03 (m, 2H), 8.84-8.75 (m, 2H), 8.47 (d, J=4.5 Hz, 1H), 7.70-7.58 (m, 3H), 7.55 (dd, J=7.6, 1.9 Hz, 1H), 7.40-7.23 (m, 3H), 4.98 (dt, J=11.5, 7.8 Hz, 1H), 4.73 (dd, J=11.6, 9.8 Hz, 1H), 4.51 (dd, J=9.8, 7.7 Hz, 1H), 3.35 (s, 3H). LC-MS R_(T)=5.04 min, m/z=415.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.04 min, ESI+ found [M+H]=415.1

Example 443 Method GZ7

1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 1-benzyl-N-(2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

The title compound was prepared from 5-bromo-1H-pyrazol-3-amine and 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid according to Method Z(Wuxi). ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.62-8.57 (m, 1H), 7.39-7.30 (m, 5H), 6.57 (s, 1H), 5.48 (s, 2H), 4.39-4.31 (m, 2H), 4.26-4.19 (m, 1H), 3.22 (s, 3H), 2.65-2.56 (m, 1H), 2.44-2.36 (m, 1H). LCMS R_(T)=1.23 min, m/z=444.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.23 min, ESI+ found [M+H]=444.0.

Examples 444-447

(R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (S)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Mixture of 64% (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and 36(S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was reduced according to Method GZ2. The crude residue was further purified by chiral SFC was purified by chiral SFC (Chiralpak ID; 150×21.2 mm, 5 um; 30% methanol isocratic elution with Carbon Dioxide) affording four isomers (structural isomers were assigned based on 1H NMR; diastereomers were arbitrarily assigned):

(R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (3 mg, 4.3%) as white solids (S)—N—((S)-6, 8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1.1 mg, 1.7%) as white solids (R)—N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-propyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1.4 mg, 2.1%) as white solids (S)—N—((S)-6, 8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (3.6 mg, 5.5%) as white solids.

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (Whelkol s,s, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.626 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.38 (d, J=7.7 Hz, 1H), 7.23 (ddd, J=10.4, 9.0, 2.9 Hz, 1H), 7.03 (dt, J=9.4, 2.2 Hz, 1H), 4.90 (dt, J=11.1, 7.4 Hz, 1H), 4.65 (t, J=10.7 Hz, 1H), 4.52 (dd, J=10.2, 7.1 Hz, 1H), 4.17 (dt, J=8.8, 4.6 Hz, 1H), 2.90 (d, J=16.6 Hz, 1H), 2.79 (td, J=12.3, 10.8, 5.0 Hz, 1H), 2.68-2.59 (m, 1H), 2.10-1.98 (m, 2H), 1.84-1.65 (m, 2H), 0.98 (d, J=7.1 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.58 min, m/z=406.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.58 min, ESI+ found [M+H]=406.1

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T) (Whelkol s,s, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.675 min, 100% purity, 100% ee:). LCMS R_(T)=4.68 min, m/z=406.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.68 min, ESI+ found [M+H]=406.1

Analytical data for the third eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (Whelkol s,s, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.918 min, 93.4% purity, 86.8% ee:). LCMS R_(T)=4.68 min, m/z=406.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.68 min, ESI+ found [M+H]=406.1

Analytical data for the fourth eluting diastereomer (arbitrarily assigned S, S configuration SFC R_(T) (Whelkol s,s, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.975 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.38 (d, J=7.7 Hz, 1H), 7.23 (ddd, J=10.4, 9.0, 2.9 Hz, 1H), 7.03 (dt, J=9.4, 2.2 Hz, 1H), 4.90 (dt, J=11.1, 7.4 Hz, 1H), 4.65 (t, J=10.7 Hz, 1H), 4.52 (dd, J=10.2, 7.1 Hz, 1H), 4.17 (dt, J=8.8, 4.6 Hz, 1H), 2.90 (d, J=16.6 Hz, 1H), 2.79 (td, J=12.3, 10.8, 5.0 Hz, 1H), 2.68-2.59 (m, 1H), 2.10-1.98 (m, 2H), 1.84-1.65 (m, 2H), 0.98 (d, J=7.1 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H). LCMS R_(T)=4.60 min, m/z=406.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.60 min, ESI+ found [M+H]=406.1

Example 448 Method GZ8

1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

The title compound was prepared from 5-bromo-1H-pyrazol-3-amine and 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid according to Method GZ7 following step 1 to step 3. LCMS R_(T)=1.08 min [2 min method], m/z=394 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.08 min, ESI+ found [M+H]=394.0.

Step 2: 1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of 3,3-difluoropyrrolidine hydrochloride (40 mg, 0.102 mmol) in dichloroethane (1 mL) was added triethylamine (0.04 mL, 0.305 mmol) and allowed to stir for 10 mins. Added 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 0.102 mmol) as one portion, sodium triacetoxyborohydride (88 mg, 0.408 mmol) was added and allowed to stir overnight. The reaction was quenched with the addition of saturated aq. NaHCO₃ solution (10 mL) and stirring for 20 min. Extracted with isopropyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, The crude residue was purified by flash column chromatography (silica gel, 0% to 10% methanol in dichloromethane) to afford 1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (69 mg, 72% Yield) as a tan solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 5H), 6.28 (s, 1H), 5.48 (s, 2H), 4.31 (qd, J=7.9, 2.4 Hz, 2H), 4.15 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 3.57 (q, J=13.4 Hz, 2H), 3.23 (s, 3H), 2.91 (t, J=13.4 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H), 2.67-2.54 (m, 1H), 2.43-2.10 (m, 3H). LC-MS R_(T)=2.88 min, m/z=485.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.88 min, ESI+ found [M+H]=485.2

Example 449

Prepared according to Method GZ8.

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.51 (d, J=7.7 Hz, 1H), 7.42-7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.36-4.24 (m, 2H), 4.14 (ddd, J=14.5, 12.5, 6.6 Hz, 1H), 3.57 (t, J=4.6 Hz, 4H), 3.48-3.32 (m, 2H), 3.23 (s, 3H), 2.59 (m, 1H), 2.50-2.29 (m, 5H). m/z=465.2 (M+H)⁺.

Example 450 Method GZ8

1-benzyl-N-(2-((3-fluoroazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-((3-fluoroazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol o[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was prepared from 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide and 3-fluoroazetidine hydrochloride according to Method GZ8 to afford final product (49 mg, 85%) as a white. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 6H), 6.23 (s, 1H), 5.48 (s, 2H), 5.26-4.98 (m, 1H), 4.35-4.23 (m, 2H), 4.14 (ddd, J=14.4, 12.5, 6.6 Hz, 1H), 3.67-3.44 (m, 5H), 3.26-3.12 (m, 6H), 2.58 (tt, J=13.5, 8.5 Hz, 1H), 2.41-2.28 (m, 1H). LC-MS R_(T)=2.58 min, m/z=453.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.58 min, ESI+ found [M+H]=453.2

Example 451

1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was prepared from 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide and 3-methoxyazetidine hydrochloride according to Method GZ8 to afford final product (36 mg, 61%) as a white. ¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.42-7.23 (m, 5H), 6.21 (s, 1H), 5.48 (s, 2H), 4.29 (ddd, J=15.8, 8.1, 2.4 Hz, 2H), 4.13 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 3.94 (p, J=5.8 Hz, 1H), 3.48 (dt, J=21.7, 13.2 Hz, 4H), 3.22 (s, 3H), 3.14 (s, 3H), 2.92-2.81 (m, 2H), 2.57 (ddd, J=12.7, 8.0, 4.9 Hz, 1H), 2.41-2.28 (m, 1H). LC-MS R_(T)=2.66 min, m/z=465.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.66 min, ESI+ found [M+H]=465.2

Example 452 Method GZ6

Step 1: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

Utilizing 3-phenylpyrazin-2-amine to replace 6-(trifluoromethyl)pyridin-2-amine in step 1 of Method GZ5, follow the steps. (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazol o[1,5-a]pyrazine-2-carboxamide was prepared corresponding from (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one, and 8-phenyl-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid according to Method GZ5. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) instead. Yield of final step: 35.5 mg, 22.9%. ¹H NMR (400 MHz, DMSO-d6) δ 9.15-9.03 (m, 2H), 8.84-8.75 (m, 2H), 8.47 (d, J=4.5 Hz, 1H), 7.70-7.58 (m, 3H), 7.55 (dd, J=7.6, 1.9 Hz, 1H), 7.40-7.23 (m, 3H), 4.98 (dt, J=11.5, 7.8 Hz, 1H), 4.73 (dd, J=11.6, 9.8 Hz, 1H), 4.51 (dd, J=9.8, 7.7 Hz, 1H), 3.35 (s, 3H). LC-MS R_(T)=5.04 min, m/z=415.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.04 min, ESI+ found [M+H]=415.1

Step 2: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

To a solution of (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazol o[1,5-a]pyrazine-2-carboxamide (368 mg, 0.88 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added platinum(iv) oxide (20.2 mg, 0.088 mmol). The reaction mixture stirred under a balloon of hydrogen gas for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% methanol in dichloromethane) to afford N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetra hydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide (216 mg, 52% Yield) as a tan solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (dd, J=8.1, 1.9 Hz, 1H), 7.49 (dt, J=7.5, 1.5 Hz, 1H), 7.44-7.11 (m, 9H), 5.20 (t, J=5.0 Hz, 1H), 4.91-4.75 (m, 1H), 4.56 (ddd, J=11.5, 9.9, 4.1 Hz, 1H), 4.37 (ddd, J=9.9, 7.6, 6.0 Hz, 1H), 4.32-4.15 (m, 2H), 3.37 (q, J=5.3 Hz, 1H), 3.32-3.11 (m, 4H). LC-MS R_(T)=3.26 min, m/z=419.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.26 min, ESI+ found [M+H]=419.1

Step 2: 1-benzyl-N-(4-methyl-5-oxo-2-vinyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of 1-benzyl-N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide (3860 mg, 8.69 mmol, 1.0 equiv) in tetrahydrofuran (80 mL) and water (20 mL) was added potassium vinyltrifluoroborate (2450 mg, 17.38 mmol, 2.0 equiv) and cesium fluoride (3959 mg, 26.06 mmol, 3.0 equiv). The mixture was then degassed for 30 mins with a nitrogen stream. To the mixture was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (647.5 mg, 0.8688 mmol, 0.10 equiv). The vessel was capped, and the reaction mixture was heated to 70° C. for 4 days. After this time the mixture was diluted with dichloromethane (100 mL) and water (150 mL). The layers were separated, and the aqueous was extracted two more times with dichloromethane (2×100 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) affording 1-benzyl-N-(4-methyl-5-oxo-2-vinyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (1070 mg, 32% yield) as a dark brown solid. LCMS R_(T)=1.17 min [2 min method], m/z=392 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.17 min, ESI+ found [M+H]=392.0.

Step 3: 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Ozone was bubbled through a solution of 1-benzyl-N-(4-methyl-5-oxo-2-vinyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (1070 mg, 2.73 mmol, 1.0 equiv) in methanol (20 mL) cooled to −78° C. for 45 mins. The reaction was quenched with dimethyl sulfide (1.01 mL, 849 mg, 13.7 mmol, 5.0 equiv) and allowed to warm to RT. The mixture was evaporated to dryness in vacuo, and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) affording 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (600 mg, 56% yield) as a yellow solid. LCMS R_(T)=1.08 min [2 min method], m/z=394 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 2 mins) retention time 1.08 min, ESI+ found [M+H]=394.0.

Step 4: 1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 0.102 mmol) and morpholine (0.026 mL, 0.305 mmol) in dichloroethane (1 mL) was added acetic acid (0.01 mL, 0.203 mmol) and allowed to stir for 30 min. Sodium triacetoxyborohydride (65 mg, 0.305 mmol) was added and allowed to stir overnight. The reaction was made basic with the addition of saturated aq. NaHCO₃ solution (10 mL) and stirring for 20 min. Extracted with isopropyl acetate (3×10 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, The crude residue was purified by flash column chromatography (silica gel, 0% to 15% methanol in dichloromethane) to afford 1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1, 3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 85% Yield) as a tan solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.51 (d, J=7.7 Hz, 1H), 7.42-7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.36-4.24 (m, 2H), 4.14 (ddd, J=14.5, 12.5, 6.6 Hz, 1H), 3.57 (t, J=4.6 Hz, 4H), 3.48-3.32 (m, 2H), 3.23 (s, 3H), 2.59 (m, 1H), 2.50-2.29 (m, 5H). LC-MS R_(T)=2.56 min, m/z=465.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.56 min, ESI+ found [M+H]=465.2

Example 453

(S)-5-Benzyl-N-(1-methyl-9,9-dioxido-2-oxo-1,2,3,4,5,10-hexahydro-8H-thieno[3′,4′:3,4]pyrazolo[1,5-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide Method AA

(10.5 mg, 38% yield for the chiral separation step)

¹H NMR (400 MHz, DMSO-d6) δ 8.47 (bs, 1H), 7.40-7.17 (m, 5H), 4.56-4.33 (m, 6H), 4.33-4.20 (m, 1H), 4.10 (s, 2H), 3.20 (s, 3H), 2.75-2.59 (m, 1H), 2.41-2.29 (m, 1H); LCMS R_(T)=3.40 min; m/z=456.1 [M+H]⁺.

Chiral SFC separation condition: 20% Methanol (containing 0.1% Ammonium Hydroxide) in Carbon dioxide; ChiralPak OJ (250×21.2 mm); 70 mL/min; 40° C.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.40 min, ESI+ found [M+H]=456.1.

Example 454

1-Benzyl-N-(2-cyclobutyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][13]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(68 mg, 73% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.46-7.27 (m, 5H), 6.23 (s, 1H), 5.48 (s, 2H), 4.38-4.23 (m, 2H), 4.17-4.05 (m, 1H), 3.52-3.38 (m, 1H), 3.23 (s, 3H), 2.39-2.06 (m, 5H), 2.02-1.76 (m, 3H); LCMS R_(T)=4.58 min; m/z=420.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.58 min, ESI+ found [M+H]=420.2.

Example 455

1-Benzyl-N-(2-isopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(52 mg, 55% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.43-7.26 (m, 5H), 6.18 (s, 1H), 5.48 (s, 2H), 4.39-4.23 (m, 2H), 4.20-4.03 (m, 1H), 3.22 (s, 3H), 2.86 (hept, J=7.0 Hz, 1H), 2.40-2.24 (m, 2H), 1.21 (d, J=6.9 Hz, 6H); LCMS R_(T)=4.08 min; m/z=408.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.08 min, ESI+ found [M+H]=408.2.

Example 456

1-Benzyl-N-(2-(cyclopropylmethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(65 mg, 69% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.50 (d, J=7.8 Hz, 1H), 7.45-7.24 (m, 5H), 6.21 (s, 1H), 5.48 (s, 2H), 4.37-4.04 (m, 3H), 3.23 (s, 3H), 2.47-2.29 (m, 4H), 1.06-0.89 (m, 1H), 0.52-0.41 (m, 2H), 0.24-0.10 (m, 2H); LCMS R_(T)=4.51 min; m/z=420.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.51 min, ESI+ found [M+H]=420.2

Example 457

(S)-1-Benzyl-N-(2-cyclobutyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(68 mg, 73% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.46-7.27 (m, 5H), 6.23 (s, 1H), 5.48 (s, 2H), 4.38-4.23 (m, 2H), 4.17-4.05 (m, 1H), 3.52-3.38 (m, 1H), 3.23 (s, 3H), 2.39-2.06 (m, 5H), 2.02-1.76 (m, 3H); LCMS R_(T)=4.60 min; m/z=420.2 [M+H]⁺.

Chiral SFC separation condition: 40% Methanol (containing 0.1% Ammonium Hydroxide) in Carbon dioxide; Cellulose-1 (150×21.2 mm); 70 mL/min; 40° C.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.60 min, ESI+ found [M+H]=420.2.

Example 458

(S)-1-Benzyl-N-(2-isopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(18 mg, 72% yield for the chiral SFC separation step)

¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.50 (d, J=7.8 Hz, 1H), 7.45-7.24 (m, 5H), 6.18 (s, 1H), 5.48 (s, 2H), 4.38-4.23 (m, 2H), 4.18-4.03 (m, 1H), 3.22 (s, 3H), 2.86 (hept, J=6.9 Hz, 1H), 2.66-2.53 (m, 1H), 2.41-2.26 (m, 1H), 1.21 (dd, J=6.9, 4.4 Hz, 6H); LCMS R_(T)=4.45 min; m/z=408.2 [M+H]⁺.

Chiral SFC separation condition: 35% Methanol in Carbon dioxide; Cellulose-1 (150×21.2 mm); 70 mL/min; 40° C.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.45 min, ESI+ found [M+H]=408.2

Example 459

(S)-1-benzyl-N-(2-(cyclopropylmethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(27.8 mg)

¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.45-7.22 (m, 5H), 6.22 (s, 1H), 5.48 (s, 2H), 4.38-4.22 (m, 2H), 4.20-4.04 (m, 1H), 3.23 (s, 3H), 2.63-2.55 (m, 1H), 2.43 (t, J=6.5 Hz, 2H), 2.39-2.28 (m, 1H), 1.03-0.93 (m, 1H), 0.52-0.42 (m, 2H), 0.25-0.12 (m, 2H); LCMS R_(T)=4.53 min; m/z=420.2 [M+H]⁺.

Chiral SFC separation condition: 35% Methanol in Carbon dioxide; Cellulose-1 (150×21.2 mm); 70 mL/min; 40° C.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.53 min, ESI+ found [M+H]=420.2

Example 460

1-Benzyl-N-(2-ethyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(10.8 mg, 10% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.44-7.26 (m, 5H), 6.16 (s, 1H), 5.48 (s, 2H), 4.40-4.23 (m, 2H), 4.15-4.04 (m, 1H), 3.22 (s, 3H), 2.62-2.51 (m, 3H), 2.40-2.25 (m, 1H), 1.18 (t, J=7.6 Hz, 3H); LCMS R_(T)=4.14 min; m/z=394.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.14 min, ESI+ found [M+H]=394.2

Example 461

1-Benzyl-N-(2-isopropoxy-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method Z

(84 mg, 73% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.43-7.26 (m, 5H), 5.79 (s, 1H), 5.48 (s, 2H), 4.68 (hepta, J=6.1 Hz, 1H), 4.37 (dt, J=11.5, 7.8 Hz, 1H), 4.15-4.02 (m, 2H), 3.20 (s, 3H), 2.64-2.53 (m, 1H), 2.39-2.25 (m, 1H), 1.28 (d, J=6.1 Hz, 3H), 1.26 (d, J=6.1 Hz, 3H); LCMS R_(T)=4.44 min; m/z=424.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.44 min, ESI+ found [M+H]=424.2

Example 462

(S)-1-Benzyl-5-methyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide Method B

(57 mg, 56% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=7.8 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.41-7.30 (m, 3H), 7.26-7.18 (m, 2H), 6.34 (d, J=2.0 Hz, 1H), 5.44 (s, 2H), 4.44-4.12 (m, 3H), 3.25 (s, 3H), 2.66-2.53 (m, 1H), 2.46 (s, 3H), 2.43-2.32 (m, 1H); LCMS R_(T)=3.78 min; m/z=380.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.78 min, ESI+ found [M+H]=380.2

Example 463

N-(2-Ethyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide Method Z

(159 mg, 61% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.50-7.15 (m, 4H), 6.16 (s, 1H), 5.55 (s, 2H), 4.39-4.22 (m, 2H), 4.14-4.00 (m, 1H), 3.22 (s, 3H), 2.62-2.52 (m, 3H), 2.41-2.25 (m, 1H), 1.18 (t, J=7.6 Hz, 3H); LCMS R_(T)=4.27 min; m/z=412.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.27 min, ESI+ found [M+H]=412.2

Example 464

(S)—N-(2-ethyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide Method Z

(78 mg, 97% yield in the chiral separation step)

¹H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.50 (d, J=7.8 Hz, 1H), 7.47-7.18 (m, 4H), 6.16 (s, 1H), 5.55 (s, 2H), 4.39-4.23 (m, 2H), 4.19-4.03 (m, 1H), 3.22 (s, 3H), 2.70-2.50 (m, 3H), 2.41-2.21 (m, 1H), 1.18 (t, J=7.6 Hz, 3H).

Example 465

(R)-5-(2-fluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

(10.8 mg, 14% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.9 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.47-7.39 (m, 1H), 7.30-7.20 (m, 3H), 6.33 (d, J=2.0 Hz, 1H), 5.77 (dd, J=8.7, 5.7 Hz, 1H), 4.42-4.09 (m, 3H), 3.28-3.17 (m, 4H), 3.14-2.97 (m, 2H), 2.70-2.53 (m, 2H), 2.43-2.27 (m, 1H).

Example 466

(S)-5-(2-fluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

(11.1 mg, 14% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=7.8 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.47-7.39 (m, 1H), 7.31-7.19 (m, 3H), 6.33 (d, J=2.0 Hz, 1H), 5.78 (dd, J=8.7, 5.7 Hz, 1H), 4.43-4.09 (m, 3H), 3.29-3.17 (m, 4H), 3.11-2.99 (m, 2H), 2.71-2.53 (m, 2H), 2.43-2.28 (m, 1H).

Example 467

(S)-5-(2-fluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

(10.8 mg, 14% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=8.0 Hz, 1H, NH), 7.52-7.47 (m, 1H), 7.47-7.40 (m, 1H), 7.34-7.19 (m, 6H), 5.78 (dd, J=8.6, 5.7 Hz, 1H), 4.81 (dt, J=11.5, 7.8 Hz, 1H), 4.58 (dd, J=11.6, 9.9 Hz, 1H), 4.39 (dd, J=9.9, 7.7 Hz, 1H), 3.30 (s, 3H), 3.27-3.18 (m, 1H), 3.16-2.95 (m, 2H), 2.70-2.54 (m, 1H).

Example 468

(R)-5-(2-fluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

(8.8 mg, 11% yield)

1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=8.0 Hz, 1H, NH), 7.53-7.45 (m, 1H), 7.47-7.39 (m, 1H), 7.35-7.19 (m, 6H), 5.78 (dd, J=8.7, 5.7 Hz, 1H), 4.81 (dt, J=11.5, 7.8 Hz, 1H), 4.57 (dd, J=11.5, 9.9 Hz, 1H), 4.39 (dd, J=9.9, 7.7 Hz, 1H), 3.31 (s, 3H), 3.28-3.17 (m, 1H), 3.11-2.98 (m, 2H), 2.68-2.56 (m, 1H).

Example 469 WX Method 135

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide

Step 1: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethanol

To a solution of 6-bromonicotinaldehyde (3.0 g, 16.13 mmol) in tetrahydrofuran (100 mL) was added (trifluoromethyl)trimethylsilane (467 mg, 3.28 mmol) and tetrabutylammoniumfluoride (0.27 ml, 0.27 mmol) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 48 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 1-(6-bromo-3-pyridyl)-2,2,2-trifluoro-ethanol (3.8 g, 92%) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=2.0 Hz, 1H), 7.77-7.74 (m, 1H), 7.57 (d, J=8.4 Hz, 1H), 5.11 (q, J=6.8 Hz, 1H).

Step 2: 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinamide

A mixture of 1-(6-bromo-3-pyridyl)-2,2,2-trifluoro-ethanol (3.8 g, 14.84 mmol) and copper(I) cyanide (2.66 g, 29.69 mmol) in 1-methyl-2-pyrrolidinone (50 mL) was heated to 130° C. for 10 h. The reaction mixture was poured into 10% ammonium hydroxide (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% ethyl acetate in petroleum ether) to afford 5-(2,2,2-trifluoro-1-hydroxy-ethyl)pyridine-2-carboxamide (2 g, 61%) as yellow oil. LCMS R_(T)=0.98 min; m/z=221.0 (M+H)⁺.

LCMS (10-80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 0.98/min, ESI+ found [M+H]=221.0.

Step 3: 1-(6-carbamoylpyridin-3-yl)-2,2,2-trifluoroethyl 4-methylbenzenesulfonate

To a solution of 5-(2,2,2-trifluoro-1-hydroxy-ethyl)pyridine-2-carboxamide (2.0 g, 9.08 mmol) in dichloromethane (50 mL) was added triethylamine (1.84 g, 18.17 mmol), p-toluenesulfonylchloride (2.60 g, 13.63 mmol) and 4-dimethylaminopyridine (222 mg, 1.82 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was poured into water (5 mL) and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford [1-(6-carbamoyl-3-pyridyl)-2,2,2-trifluoro-ethyl]4-methylbenzenesulfonate (1.8 g, 53%) as white solid. LCMS R_(T)=0.72 min; m/z=374.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.72 min, ESI+ found [M+H]=374.9.

Step 4:1-(6-cyanopyridin-3-yl)-2,2,2-trifluoroethyl 4-methylbenzenesulfonate

A solution of [1-(6-carbamoyl-3-pyridyl)-2,2,2-trifluoro-ethyl] 4-methylbenzenesulfonate (1.8 g, 4.81 mmol) in tetrahydrofuran (100 mL) was treated with triethylamine (1.46 g, 14.43 mmol) and trifluoroacetic anhydride (1.52 g, 7.21 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 33% ethyl acetate in petroleum ether) to afford [1-(6-cyano-3-pyridyl)-2,2,2-trifluoro-ethyl] 4-methylbenzenesulfonate (1.5 g, 87%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.92-7.90 (m, 1H), 7.74-7.70 (m, 3H), 7.34-7.32 (m, 1H), 5.75 (q, J=6.8 Hz, 1H), 2.46 (s, 3H).

Step 5: tert-butyl ((5-(2,2,2-trifluoroethyl)pyridin-2-yl)methyl)carbamate

A mixture of [1-(6-cyano-3-pyridyl)-2,2,2-trifluoro-ethyl] 4-methylbenzenesulfonate (1.30 g, 3.65 mmol), Pd/C (10%, 389 mg, 0.37 mmol) and hydrochloric acid (36%, 1.11 g, 10.95 mmol) in methanol (100 mL) was hydrogenated (50 psi) for 24 h. The reaction mixture was filtered and the filtrate was adjusted to pH=10 by addition of 2N sodium hydroxide (1 mL) and then di-tert-butyldicarbonate (1.59 g, 7.30 mmol) was added to the above solution. The reaction mixture was stirred at 25° C. for 10 h and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford tert-butyl N-[[5-(2,2,2-trifluoroethyl)-2-pyridyl]methyl]carbamate (1.0 g, 94%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s 1H), 7.64 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 5.54 (s, 1H), 4.47-4.45 (m, 2H), 3.40 (q, J=6.8 Hz, 2H), 1.47 (s, 9H).

Step 6: (5-(2,2,2-trifluoroethyl)pyridin-2-yl)methanamine hydrochloride

A solution of tert-butyl N-[[5-(2,2,2-trifluoroethyl)-2-pyridyl]methyl]carbamate (1.0 g, 3.44 mmol) in ethyl acetate (20 mL) was treated with hydrochloric acid (4N in ethyl acetate, 4.0 mL, 16.0 mmol). The resulting mixture was stirred at 25° C. for 1 h and concentrated under reduced pressure to afford crude [5-(2,2,2-trifluoroethyl)-2-pyridyl]methanamine hydrochloride (800 mg, 100%) as white solid, used as is in the next step.

Step 7: Ethyl 2-oxo-2-(((5-(2,2,2-trifluoroethyl)pyridin-2-yl)methyl)amino)acetate

A mixture of [5-(2,2,2-trifluoroethyl)-2-pyridyl]methanamine hydrochloride (300 mg, 1.32 mmol) and triethylamine (536 mg, 5.29 mmol) in tetrahydrofuran (20 mL) was treated with ethyl oxalyl chloride (271 mg, 1.99 mmol) at 0° C. After addition, the reaction mixture was stirred to 25° C. for 5 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude ethyl 2-oxo-2-[[5-(2,2,2-trifluoroethyl)-2-pyridyl]methyl amino]acetate (400 mg, 100%) as a brown solid. LCMS R_(T)=0.53 min; m/z=290.8 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.53 min, ESI+ found [M+H]=290.8.

Step 8: Ethyl 6-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridine-3-carboxylate

A mixture of ethyl 2-oxo-2-[[5-(2,2,2-trifluoroethyl)-2-pyridyl]methylamino]acetate (350 mg, 1.21 mmol) and phosphorus oxychloride (16.88 g, 110.09 mmol) was heated to 110° C. for 10 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford methyl 6-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridine-3-carboxylate (150 mg, 48%) as a brown solid.

¹H NMR (400 MHz, CDCl₃) δ 9.34 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.65-7.63 (m, 2H), 7.04-7.02 (m, 1H), 4.52(q, J=6.8 Hz, 2H), 3.40 (q, J=6.8 Hz, 2H), 1.49 (t, J=4.2 Hz, 2H).

Step 9: Ethyl 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

A mixture of ethyl 6-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridine-3-carboxylate (150 mg, 0.55 mmol) and Pd/C (10%, 30 mg) in methanol (10 mL) was hydrogenated (50 psi) at 50° C. for 10 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) to afford methyl 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (100 mg, 69%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.95 (s, 1H), 4.84-4.79 (m, 1H), 3.94-3.85 (m, 4H), 3.02-2.97 (m, 1H), 2.83-2.82 (m, 1H), 2.38-2.09 (m, 5H).

Step 10: Potassium 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate

A mixture of methyl 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (30 mg, 0.11 mmol) in water (1 mL) and tetrahydrofuran (2 mL) was treated with potassium hydroxide (12 mg, 0.23 mmol). The resulting mixture was stirred at 25° C. for 1 hand then concentrated under reduced pressure to afford crude potassium 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (30 mg, 92%) as a white solid, used is as in the next step.

Step 11: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide

A mixture of potassium 6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxylate (30 mg, 0.10 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (24 mg, 0.13 mmol) and (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (65 mg, 0.13 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 10 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (40% to 70% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carboxamide (6.6 mg, 15%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ7.44-7.41 (m, 1H), 7.32-7.29 (m, 2H), 7.24-7.22 (m, 1H), 6.83 (s, 1H), 4.95-4.90 (m, 1H), 4.85-4.80 (m, 1H), 4.60-4.55 (m, 1H), 4.38-4.34 (m, 1H), 3.85-3.83 (m, 1H), 3.41 (s, 3H), 3.01-2.96 (m, 1H), 2.80-2.78 (m, 1H), 2.35-2.30 (m, 3H), 2.08-2.05 (m, 1H), 1.62-1.60 (m, 1H). LCMS R_(T)=2.52 min, m/z=423.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 2.52 min, ESI+ found [M+H]=423.1.

Example 470 WX Method 001

N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydrofuran-2-ylmethyl)-1,2,4-triazole-3-carboxamide

A mixture of potassium carbonate (328 mg, 2.38 mmol), N-[(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazzolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (150 mg, 0.48 mmol) and 2-(bromomethyl)tetrahydrofuran (160 mg, 0.97 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 15 h. The mixture was filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 13-43%/0.05% ammonia hydroxide in water) to afford N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydrofuran-2-ylmethyl)-1,2,4-triazole-3-carboxamide (29.1 mg, 15%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 6.01 (s, 1H), 4.56-4.51 (m, 1H), 4.38-4.23 (m, 5H), 3.84-3.74 (m, 2H), 3.32 (s, 3H), 2.87-2.85 (m, 1H), 2.27-2.25 (m, 1H), 2.25-2.23 (m, 1H), 1.94-1.87 (m, 3H), 1.83-1.81 (m, 1H), 0.95-0.92 (m, 2H), 0.75-0.73 (m, 2H). LC-MS R_(T)=0.700 min, m/z=400.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.700 min, ESI+ found [M+H]=400.1.

Example 471

1-[(3,5-difluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (methanol 50-80%/0.05% ammonia hydroxide in water) to afford 1-[(3,5-difluorophenyl)methyl]-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5][1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (28 mg, 32%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.61 (s, 1H), 6.96-6.90 (m, 3H), 6.10 (s, 1H), 5.48 (s, 2H), 4.54-4.49 (m, 1H), 4.2-4.27 (m, 1H), 4.24-4.19 (m, 1H), 3.29 (m, 3H), 2.85-2.79 (m, 1H), 2.28-2.21 (m, 4H). LC-MS R_(T)=0.756 min, m/z=416.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.756 min, ESI+ found [M+H]=416.1.

Example 472

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (60 mg, 0.21 mmol), 1-(bromomethyl)-2,3-dichloro-benzene (59 mg, 0.25 mmol) and potassium carbonate (86 mg, 0.62 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (methanol 55-85%/0.05% ammonia hydroxide in water) to afford (1-[(2,3-dichlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (19.4 mg, 21%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 7.55-7.53 (m, 1H), 7.33-7.29 (m, 1H), 7.22-7.20 (m, 1H), 6.09 (s, 1H), 5.63 (s, 2H), 4.53-4.48 (m, 1H), 4.29-4.27 (m, 1H), 4.22-4.15 (m, 1H), 3.30 (s, 3H), 2.85-2.78 (m, 1H), 2.27-2.20 (m, 4H). LCMS R_(T)=0.791 min, m/z=448.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.791 min, ESI+ found [M+H]=448.1.

Example 473

1-[(2,4-dichlorophenyl)methyl]-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (methanol 60-90%/0.05% ammonia hydroxide in water) to give 1-[(2,4-dichlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (16.7 mg, 18%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.59 (s, 1H), 7.52 (s, 1H), 7.41-7.30 (m, 2H), 5.99 (s, 1H), 5.57 (s, 2H), 4.53-4.48 (m, 1H), 4.28-4.26 (m, 1H), 4.20-4.17 (m, 1H), 3.29 (s, 3H), 2.85-2.78 (m, 1H), 2.27-2.22 (m, 1H), 1.91-1.86 (m, 1H), 0.92-0.91 (m, 2H), 0.77-0.71 (m, 2H). LC-MS R_(T)=0.831 min, m/z=474.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.831 min, ESI+ found [M+H]=474.1.

Example 474

N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydrofuran-2-ylmethyl)-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (acetonitrile 12-42%/0.05% ammonia hydroxide in water) to afford N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydrofuran-2-ylmethyl)-1,2,4-triazole-3-carboxamide (68.1 mg, 35%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 6.12 (s, 1H), 4.55-4.53 (m, 1H), 4.41-4.18 (m, 5H), 3.83 (q, J=6.8 Hz, 1H), 3.78-3.71 (m, 1H), 3.33 (s, 3H), 2.91-2.82 (m, 1H), 2.33-2.19 (m, 4H), 2.12-2.05 (m, 1H), 1.94-1.79 (m, 2H), 1.73-1.65 (m, 1H). LC-MS R_(T)=1.114 min, m/z=374.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.114 min, ESI+ found [M+H]=374.2.

Example 475

N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-3-ylmethyl)-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (acetonitrile 22-32%/0.05% ammonia hydroxide in water), and the partially epimerized material was further purified by chiral SFC to afford N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-3-ylmethyl)-1,2,4-triazole-3-carboxamide (Peak 1, (Retention time=1.699 min) & Peak 2 (Retention time=1.883 min)) (21.2 mg, 52%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ8.48 (s, 1H), 6.12 (s, 1H), 4.53-4.51 (m, 1H), 4.31-4.19 (m, 4H), 3.76-3.74 (m, 2H), 3.48-3.46 (m, 1H), 3.33 (s, 3H), 3.31-3.25 (m, 1H), 2.85-2.83 (m, 1H), 2.28-2.22 (m, 5H), 1.73-1.70 (m, 2H), 1.60-1.50 (m, 1H), 1.34-1.31 (m, 1H). LC-MS R_(T)=1.176 min, m/z=388.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.176 min, ESI+ found [M+H]=388.1.

SFC condition: column: chiralcel OD-3 50×4.6 mm I.D., 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: hold 5% for 0.2 min, then from 5% to 40% of Bin 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example 476

N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-2-ylmethyl)-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonia hydroxide in water) to give N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-2-ylmethyl)-1,2,4-triazole-3-carboxamide (10 mg, 5%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 6.11 (s, 1H), 4.54-4.40 (m, 1H), 4.37-4.17 (m, 4H), 3.96-3.87 (m, 1H), 3.76-3.67 (m, 1H), 3.38-3.31 (m, 4H), 2.93-2.78 (m, 1H), 2.26 (s, 4H), 1.86 (s, 1H), 1.67-1.65 (m, 1H), 1.61-1.46 (m, 3H), 1.34-1.20 (m, 1H) LC-MS R_(T)=1.298 min, m/z=388.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.298 min, ESI+ found [M+H]=388.2.

Example 477

N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-2-ylmethyl)-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonia hydroxide in water) to give N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-2-ylmethyl)-1,2,4-triazole-3-carboxamide (38 mg, 19%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 6.03 (s, 1H), 4.55-4.53 (m, 1H), 4.37-4.13 (m, 4H), 3.93-3.82 (m, 1H), 3.79-3.67 (m, 1H), 3.44-3.36 (m, 1H), 3.34 (s, 3H), 2.94-2.80 (m, 1H), 2.31-2.23 (m, 1H), 2.00-1.83 (m, 2H), 1.71-1.68 (m, 1H), 1.63-1.48 (m, 3H), 1.39-1.21 (m, 1H), 0.97-0.94 (m, 2H), 0.84-0.68 (m, 2H). LC-MS R_(T)=1.458 min, m/z=414.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.458 min, ESI+ found [M+H]=414.2.

Example 478

N-(6S-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-3-ylmethyl)-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (acetonitrile 20-50%/0.05% ammonia hydroxide in water) to give N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydropyran-3-ylmethyl)-1,2,4-triazole-3-carboxamide (27.4 mg, 14%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.48 (s, 1H), 6.00 (s, 1H), 4.54-4.53 (m, 1H), 4.30-4.20 (m, 4H), 3.76-3.73 (m, 2H), 3.50-3.46 (m, 1H), 3.31 (s, 3H), 3.28-3.27 (m, 1H), 2.90-2.85 (m, 1H), 2.26-2.21 (m, 2H), 1.91-1.90 (m, 1H), 1.80-1.70 (m, 2H), 1.70-1.65 (m, 1H), 1.40-1.35 (m, 1H), 0.94-0.92 (m, 2H), 0.75-0.70 (m, 2H). LC-MS R_(T)=1.781 min, m/z=414.2 [M+H]⁺.

LCMS (0 to 60% ammonium hydroxide in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.781 min, ESI+ found [M+H]=414.2

Example 479

N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydrofuran-3-ylmethyl)-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (acetonitrile 42-62%/0.05% ammonia hydroxide in water) to give N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydrofuran-3-ylmethyl)-1,2,4-triazole-3-carboxamide (19.1 mg, 10%) as white solids. ¹H NMR (CD₃OD) δ 8.53 (s, 1H), 6.12 (s, 1H), 4.57-4.54 (m, 1H), 4.36-4.18 (m, 4H), 3.93-3.86 (m, 1H), 3.82-3.71 (m, 2H), 3.62-3.60 (m, 1H), 3.34 (s, 3H), 2.92-2.80 (m, 2H), 2.31-2.22 (m, 4H), 2.11-2.01 (m, 1H), 1.76-1.66 (m, 1H). LC-MS R_(T)=1.383 min, m/z=374.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.383 min, ESI+ found [M+H]=374.2

Example 480

N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-(tetrahydrofuran-3-ylmethyl)-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 001. The crude was purified by RP-HPLC (acetonitrile 42-62%/0.05% ammonia hydroxide in water) to give N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][[1,3]diazepin-6-yl-1-(tetrahydrofuran-3-ylmethyl)-1,2,4-triazole-3-carboxamide (20.1 mg, 11%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 6.02 (s, 1H), 4.56-4.54 (m, 1H), 4.35-4.15 (m, 4H), 3.95-3.90 (m, 1H), 3.82-3.71 (m, 2H), 3.62-3.60 (m, 1H), 3.32 (s, 3H), 2.92-2.80 (m, 2H), 2.30-2.26 (m, 1H), 2.11-2.01 (m, 1H), 1.95-1.87 (m, 1H), 1.76-1.66 (m, 1H), 0.98-0.91 (m, 2H), 0.78-0.71 (m, 2H). LC-MS R_(T)=0.813 min, m/z=400.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 0.813 min, ESI+ found [M+H]=400.3

Example 481 WX Method 164

N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]p yrimidine-7,1′-cyclopentane]-2-carboxamide

Step 1: 2′-chloro-5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidin]-5′-one

To a solution of 2,2,6,6-tetramethylpiperidine (26.73 g, 189.2 mmol) in tetrahydrofuran (140 mL) was added n-butyllithium (2.5 M in hexanes, 100.0 mL, 250.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 2-chloropyrimidine-5-carboxylic acid (10.0 g, 63.1 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and cyclopentanone (10.61 g, 126.2 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 2′-chloro-5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidin]-5′-one (2.5 g, 18%) as white solid, used as is in the next step.

Step 2: 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-5-ol

To a solution of 2′-chlorospiro[cyclopentane-1,7′-furo[3,4-d]pyrimidin]-5′-one (1.0 g, 4.45 mmol) in toluene (20 mL) was added diisobutylaluminumhydride (13.4 mL, 13.35 mmol, 1.0 M in toluene) at −78° C. The reaction mixture was stirred at −78° C. for 2 h and quenched by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7, 1′-cyclopentane]-5-ol (800 mg, 79%) as yellow oil, used as is in the next step.

Step 3: 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]

To a solution of 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-5-ol (800 mg, 3.53 mmol) and trifluoroacetic acid (4.02 g, 35.30 mmol) in dichloromethane (20 mL) was added triethylsilane (4.10 g, 35.30 mmol) at 0° C. The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane] (300 mg, 40%) as yellow oil, used as is in the next step.

Step 4: 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidin]-2′-carbonitrile

To a solution of 2-chlorospiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane] (300 mg, 1.42 mmol) in dimethyl sulfoxide (10 mL) and water (5 mL) was added 1,4-diazabicyclo[2.2.2]octane (174 mg, 1.55 mmol) and sodium cyanide (120 mg, 2.45 mmol). The reaction mixture was stirred at 20° C. for 16 h and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL), birne (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidin]-2′-carbonitrile (250 mg, 87%) as yellow oil, used as is in the next step.

Step 5: methyl 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylate

To a solution of 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidine]-2′-carbonitrile (250 mg, 1.24 mmol) in methanol (3 mL) was added HCl (4N in methanol, 1.6 mL). The reaction mixture was heated to 70° C. for 2 h and concentrated under reduced pressure to afford crude methyl 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylate (200 mg, 69%) as yellow oil, used as is in the next step.

Step 6: 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylic acid

A mixture of methyl 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylate (200 mg, 0.85 mmol) and lithium hydroxide hydrate (358 mg, 8.54 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred at 20° C. for 2 h. The mixture was quenched by addition of 1N HCl (3 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylic acid (120 mg, 64%) as yellow oil, used as is in the next step.

Step 7: N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide

A mixture of (3S)-3-amino-6,8-difluoro-3,5-dihydro-2H-1,5-benzoxazepin-4-one (30 mg, 0.14 mmol), 5′H-spiro[cyclopentane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylic acid (36 mg, 0.16 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (25 mg, 0.19 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (40 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 40% to 70%/0.05% ammonium hydroxide in water) to afford N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide (19.5 mg, 33%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.80 (s, 1H), 6.97-6.87 (m, 2H), 5.12-5.09 (m, 3H), 4.78-4.73 (m, 1H), 4.57-4.51 (m, 1H), 2.14-2.00 (m, 4H), 1.98-1.87 (m, 4H). LCMS R_(T)=0.718 min, m/z=416.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.05% ammonium hydroxide over 1.5 mins) retention time 0.718 min, ESI+ found [M+H]=416.9.

Example 482

N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 164. The crude was purified by RP-HPLC (35% to 65% acetonitrile/0.05% ammonia hydroxide in water) to give N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide (25 mg, 55%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.80 (s, 1H), 7.46-7.44 (m, 1H), 7.34-7.32 (m, 2H), 7.27-7.24 (m, 1H), 5.12 (s, 2H), 5.07-5.02 (m, 1H), 4.69-4.68 (m, 1H), 4.46-4.43 (m, 1H), 3.44 (s, 3H), 2.08-2.04 (m, 4H), 1.95-1.93 (m, 4H). LC-MS R_(T)=2.21 min, m/z=395.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 2.21 min, ESI+ found [M+H]=395.2.

Example 483 WX Method 011

N—(S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1R,3S)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 1-(((1R,3R)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-(((1R,3R)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylate (140 mg, 0.53 mmol) and lithium hydroxide hydrate (112 mg, 2.66 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25° C. for 1 h. The solution was diluted with water (10 mL) and adjusted to pH=4-5 with addition of 1M HCl. The resulting solid was collected by filtration and dried under reduced pressure to give crude 1-(((1R,3R)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid (100 mg, 76%) as a white solids, used as is in the next step.

Step 2: N—(S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1R,3S)-3-trifluoromethylcyclobutyl)methyl)-1H-H-1,2,4-triazole-3-carboxamide

A mixture of 1-(((1R,3R)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid (31 mg, 0.12 mmol), 1-hydroxybenzotriazole (25 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (36 mg, 0.19 mmol) and (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (24 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonium hydroxide in water) to afford N—(S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1R,3 S)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (20.5 mg, 40%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.51 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.40-4.22 (m, 4H), 3.34 (s, 3H), 2.96-2.83 (m, 3H), 2.30-2.27 (m, 6H), 2.18-2.12 (m, 2H). LC-MS R_(T)=0.940 min, m/z=426.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.940 min, ESI+ found [M+H]=426.3.

Example 484

5-[(4-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 011. The crude was purified by RP-HPLC (acetonitrile 12-42%/0.05% ammonia hydroxide in water) to afford 5-[(4-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (10.54 mg, 9%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.28 (dd, J=5.2, 8.0 Hz, 2H), 7.02 (t, J=8.8 Hz, 2H), 6.09 (s, 1H), 4.48-4.53 (m, 1H), 4.19-4.34 (m, 2H), 4.05-4.17 (m, 2H), 3.16-3.28 (m, 3H), 2.77-2.85 (m, 1H), 2.14-2.28 (m, 4H). LC-MS R_(T)=0.733 min, m/z=398.1 (M+H).

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.733 min, ESI+ found [M+H]=398.1.

Example 485 WX Method 147

1-cyclopentyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: 6-chloro-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine

A mixture of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 3.23 mmol), potassium carbonate (894 mg, 6.47 mmol) and cyclopentyl bromide (506 mg, 3.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to give 6-chloro-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine (350 mg, 47%) as a colorless oil.

LCMS R_(T)=1.064 min; m/z=223.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.064 min, ESI+ found [M+H]=223.1.

Step 2: 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

To a solution of 6-chloro-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.35 mmol) in dimethyl sulfoxide (10 mL) were added 1,4-diazabicyclo[2.2.2]octane (15 mg, 0.13 mmol) and sodium cyanide (132 mg, 2.69 mmol) in water (1 mL). The mixture was stirred at 25° C. for 16 h and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (25% ethyl acetate in petroleum ether) to afford 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (80 mg, 28%) as a yellow solid.

LCMS R_(T)=1.064 min; m/z=214.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.064 min, ESI+ found [M+H]=214.1.

Step 3: methyl 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

A solution of 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (80 mg, 0.38 mmol) in methanol (5 mL) was added HCl (4N in methanol, 1.5 mL). The mixture was stirred at 20° C. for 20 h and 50° C. for 3 h. The reaction solution was concentrated under reduced pressure to give crude methyl 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (90 mg, 97%) as a yellow solid, used as is in the next step. LCMS R_(T)=0.928 min; m/z=247.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.928 min, ESI+ found [M+H]=247.1.

Step 4: 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

A mixture of methyl 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (30 mg, 0.12 mmol) and lithium hydroxide hydrate (26 mg, 0.61 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25° C. for 2 h. The organic solvent was removed under reduced pressure and the aqueous phase was adjusted to pH=4 by addition of 1N HCl. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give crude 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (25 mg, 88%) as a yellow solid. LCMS R_(T)=0.978 min; m/z=233.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.978 min, ESI+ found [M+H]=233.1.

Step 5: 1-cyclopentyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mmol), 1-cyclopentylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (25 mg, 0.11 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (25 mg, 0.13 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35% to 65%/0.05% ammonia hydroxide in water) to give 1-cyclopentyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (26.8 mg, 61%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 9.13 (d, J=8.0 Hz, 1H), 8.51 (s, 1H), 7.54-7.51 (m, 1H), 7.35-7.27 (m, 3H), 5.47-5.41 (m, 1H), 4.93-4.88 (m, 1H), 4.61-4.52 (m, 2H), 3.35 (s, 3H), 2.17-2.14 (m, 2H), 2.00-1.91 (m, 4H), 1.74-1.71 (m, 2H). LCMS R_(T)=0.836 min; m/z=407.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.836 min, ESI+ found [M+H]=407.1.

Example 486 WX Method 153

7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide

Step 1: 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)furo[3,4-d]pyrimidin-5(7H)-one

To a solution of 2,2,6,6-tetramethylpiperidine (13.5 g, 95.6 mmol) in tetrahydrofuran (300 mL) was added n-butyllithium (2.5 M in hexanes, 50.0 mL, 125.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 2-chloropyrimidine-5-carboxylic acid (5.0 g, 31.7 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and 4,4,4-trifluorobutan-2-one (4.0 g, 31.74 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)furo[3,4-d]pyrimidin-5(7H)-one (1.0 g, 12%) as yellow oil, used as is in the next step.

Step 2: 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

To a solution of 6-chloro-1-methyl-1-(2,2,2-trifluoroethyl)furo[3,4-c]pyridin-3(1H)-one (1.0 g, 3.75 mmol) in dry toluene (15 mL) was added diisobutylaluminum hydride (7.5 mL, 7.50 mmol, 1.0 M in toluene) at −70° C. The resulting solution was stirred at −70° C. for 2 h and quenched by addition of saturated ammonium chloride (10 mL). The mixture was filtered and the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were w dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (450 mg, 45%) as yellow oil, used as is in the next step.

Step 3: 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro[3,4-d]pyrimidine

To a solution of 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro [3,4-d]pyrimidin-5-ol (450 mg, 1.68 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (1.91 g, 16.75 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and triethyl silane (974 mg, 8.38 mmol) was added. After addition, the mixture was stirred for 3 hours at 25° C. and quenched by addition of saturated sodium bicarbonate solution (20 mL). The resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to afford 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5,7-dihydrofuro[3,4-d]pyrimidine (350 mg, 83%) as yellow oil, used as is in the next step.

Step 4: 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carbonitrile

To a solution of 2-chloro-7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine (350 mg, 1.39 mmol) in dimethyl sulfoxide (6 mL) and water (3 mL) was added 1,4-diazabicyclo[2.2.2]octane (155 mg, 1.39 mmol) and sodium cyanide (160 mg, 3.26 mmol). The reaction mixture was stirred at 25° C. for 3 h and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carbonitrile (130 mg, 39%) as yellow oil, used as is in the next step.

Step 5: methyl 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylate

To a solution of 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carbonitrile (130 mg, 0.53 mmol) in methanol (5 mL) was added HCl (4N in methanol, 5 mL). The reaction mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure to afford crude methyl 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylate (120 mg, 81%) as a white solid, used as is in the next step.

Step 6: 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylic acid

A mixture of methyl 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]5 pyrimidine-2-carboxylate (120 mg, 0.43 mmol) and lithium hydroxide hydrate (182 mg, 4.34 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25° C. for 1 h. The organic solvent was evaporated under reduced pressure and the aqueous phase was adjusted to pH=5 by addition of 1N HCl. The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried as washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford crude 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylic acid (90 mg, 79%) as yellow oil, used as is in the next step.

Step 7: 7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (20 mg, 0.10 mmol), 7-methyl-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylic acid (27 mg, 0.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (14 mg, 0.10 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (20 mg, 0.10 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 28% to 58%/0.05% hydrochloric acid in water) to afford 7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide (19.4 mg, 42%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.88 (s, 1H), 7.45-7.24 (m, 4H), 5.25-5.21 (m, 2H), 5.08-5.02 (m, 1H), 4.69-4.65 (m, 1H), 4.48-4.43 (m, 1H), 3.43 (s, 3H), 2.97-2.85 (m, 2H), 1.57 (s, 3H).

LCMS R_(T)=0.806 min, m/z=437.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.806 min, ESI+ found [M+H]=437.1.

Example 487

7-methyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 153. The crude was purified by RP-HPLC (acetonitrile 25% to 55%/0.05% ammonium hydroxide in water) to give 7-methyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-7-(2,2,2-trifluoroethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide (22.2 mg, 49%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.50 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.31-4.22 (m, 4H), 3.33 (s, 3H), 3.01-2.83 (m, 3H), 2.28-2.24 (m, 6H), 2.01-1.98 (m, 2H).

LCMS R_(T)=0.682 min, m/z=439.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.682 min, ESI+ found [M+H]=439.2.

Example 488 WX Method 176

4-(1-hydroxy-1-methyl-propyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyridine-2-carboxamide

Step 1: 2-(2-chloropyridin-4-yl)butan-2-ol

To a solution of 4-bromo-2-chloropyridine (5.0 g, 26.0 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M in hexanes, 13.5 mL, 33.8 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h and methyl ethyl ketone (2.81 g, 39.0 mmol) was added dropwise. The resulting mixture was allowed to warm to 25° C. over 15 h and quenched by addition of saturated ammonium chloride. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 2-(2-chloropyridin-4-yl)butan-2-ol (500 mg, 10%) as colorless oil. LCMS R_(T)=0.584 min; m/z=185.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.584 min, ESI+ found [M+H]=185.8.

Step 2: methyl 4-(2-hydroxybutan-2-yl)picolinate

A mixture of 2-(2-chloropyridin-4-yl)butan-2-ol (200 mg, 1.1 mmol), triethylamine (327 mg, 3.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride) (79 mg, 0.1 mmol) in methanol (50 mL) was heated at 70° C. for 15 h under CO (35 psi) and filtered. The filtrate was concentrated under reduce pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 4-(2-hydroxybutan-2-yl)picolinate (100 mg, 44%) as light yellow oil.

Step 3: 4-(2-hydroxybutan-2-yl)picolinic acid

A mixture of 4-(2-hydroxybutan-2-yl)picolinate (100 mg, 0.48 mmol) and potassium hydroxide (54 mg, 0.96 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure and the residue was diluted with water (10 mL). The solution was adjusted to pH=4 by addition of 2N HCl. The mixture was concentrated under reduced pressure to afford crude 4-(2-hydroxybutan-2-yl)picolinic acid (80 mg, 72%) as a yellow solid, used as is in the next step.

Step 4: 4-(1-hydroxy-1-methyl-propyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyridine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (51 mg, 0.26 mmol), 4-(1-hydroxy-1-methyl-propyl)pyridine-2-carboxylic acid (77 mg, 0.39 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (53 mg, 0.39 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (76 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 28% to 58%/0.05% ammonia hydroxide in water) to give 4-(1-hydroxy-1-methyl-propyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyridine-2-carboxamide (7.0 mg, 7.2%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.65-7.61 (m, 1H), 7.46-7.41 (m, 1H), 7.36-7.29 (m, 2H), 7.27-7.22 (m, 1H), 5.06-4.99 (m, 1H), 4.68-4.62 (m, 1H), 4.59 (s, 1H), 4.44-4.37 (m, 1H), 3.43 (s, 3H), 1.85-1.77 (m, 2H), 1.50 (s, 3H), 0.76 (t, J=4.0 Hz, 3H). LCMS R_(T)=1.00 min; m/z=370.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.00 min, ESI+ found [M+H]=370.2

Example 489 WX Method 158

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxamide

Step 1: 6-chlorospiro[furo[3,4-c]pyridine-1,3′-tetrahydropyran]-3-one

To a solution of 2,2,6,6-tetramethylpiperidine (2.69 g, 19.0 mmol) in tetrahydrofuran (60 mL) was added n-butyllithium (2.5 M in hexanes, 10.2 mL, 25.4 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 6-chloronicotinic acid (1.0 g, 6.4 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and dihydro-2H-pyran-3(4H)-one (1.27 g, 12.7 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 6-chlorospiro[furo[3,4-c]pyridine-1,3′-tetrahydropyran]-3-one (1.2 g, 79%) as a light yellow solid. LCMS R_(T)=0.595 min; m/z=240.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.595 min, ESI+ found [M+H]=240.0

Step 2: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-3-ol

To a mixture of 6-chlorospiro[furo[3,4-c]pyridine-1,3′-tetrahydropyran]-3-one (1.2 g, 5.0 mmol) in toluene (60 mL) was added diisobutylaluminum hydride (12.0 mL, 12.0 mmol, 1.0 M in toluene) at −78° C. The reaction was stirred at −78° C. for 2 h and quenched by addition of saturated ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-3-ol (1.0 g, 76%) as colorless oil.

LCMS R_(T)=0.552 min; m/z=242.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.552 min, ESI+ found [M+H]=242.0

Step 3: 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]

To a mixture of 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-3-ol (1.0 g, 4.1 mmol) and 2,2,2-trifluoroacetic acid (2.36 g, 20.7 mmol) in dichloromethane (20 mL) was added triethylsilane (1.44 g, 12.4 mmol) at 0° C. The mixture was stirred for 2 h and then adjusted to pH=8 by addition of 1N sodium hydroxide. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 mL). The solution was washed with water (2×50 mL), brine (40 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran] (800 mg, 86%) as yellow oil.

Step 4: methyl spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxylate

A mixture of 6-chlorospiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran] (800 mg, 3.55 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride (259 mg, 0.35 mmol) in methanol (100 mL) was stirred at 80° C. for 16 h under CO (25 psi) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give methyl spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxylate (810 mg, 92%) as colorless oil. LCMS R_(T)=0.570 min; m/z=250.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.570 min, ESI+ found [M+H]=250.1

Step 5: spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxylic acid

A mixture of methyl spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxylate (200 mg, 0.80 mmol) and lithium hydroxide (58 mg, 2.41 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was stirred at 25° C. for 3 h. The mixture was adjusted to pH=6 by addition of 1N HCl. The resulting solution was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxylic acid (150 mg, 80%) as a white solid, used as is in the next step.

Step 6: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (20 mg, 0.10 mmol), spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxylic acid (37 mg, 0.16 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (21 mg, 0.16 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 45% to 75%/0.05% formic acid in water) to give N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxamide (3.1 mg, 7%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.60 (s, 1H), 8.03 (s, 1H), 7.46-7.43 (m, 1H), 7.33-7.32 (m, 2H), 7.26-7.24 (m, 1H), 5.20 (d, J=8.0 Hz, 2H), 5.05-5.00 (m, 1H), 4.67-4.62 (m, 1H), 4.43-4.38 (m, 1H), 3.82 (s, 1H), 3.73-3.72 (m, 1H), 3.65-3.64 (m, 2H), 3.43 (s, 3H), 2.03-2.00 (m, 3H), 1.97-1.74 (m, 1H).

LCMS R_(T)=1.722 min; m/z=410.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide over 3 mins) retention time 1.722 min, ESI+ found [M+H]=410.1.

Example 490

5-[(2,3-difluorophenyl)methyl]-N-(6S)-2,3,4-trimethyl-5-oxo-7,8-dihydro-6H-pyrazolo 11, 5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 011. The crude was purified by RP-HPLC (ACN 25-55%/0.05% ammonia hydroxide in water) to afford 5-[(2,3-difluorophenyl)methyl]-N-(6S)-2,3,4-trimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (12.03 mg, 12%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.20-7.10 (m, 3H), 4.43-4.38 (m, 1H), 4.23-4.19 (m, 4H), 3.30 (s, 3H), 2.78-2.71 (m, 1H), 2.20-2.18 (s, 4H), 2.01 (s, 3H). LC-MS R_(T)=0.749 min, m/z=430.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.749 min, ESI+ found [M+H]=430.1

Example 491 WX Method 009

1-[(3-methylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazol[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: (3-methylcyclobutyl)methanol

To a solution of 3-methylcyclobutanecarboxylic acid (500 mg, 4.38 mmol) in tetrahydrofuran (15 mL) was added LiAlH₄ (333 mg, 8.76 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then quenched by addition of water (0.2 mL), 15% aqueous NaOH (0.2 mL) and water (0.6 mL). The mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (3-methylcyclobutyl)methanol (400 mg, 91%) as a colorless oil which was used in next step without further purification, used as is in the next step.

Step 2: (3-methylcyclobutyl)methyl 4-methylbenzenesulfonate

To a solution of (3-methylcyclobutyl)methanol (300 mg, 3.0 mmol) in dichloromethane (6 mL) was added 4-dimethylaminopyridine (642 mg, 5.3 mmol) and p-toluenesulfonylchloride (601 mg, 3.2 mmol). The reaction mixture was stirred at 20° C. for 3 h and then quenched by addition of brine (6 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (10% ethyl acetate in petroleum ether, Rf=0.5) to afford (3-methylcyclobutyl)methyl 4-methylbenzenesulfonate (450 mg, 59%) as a colorless oil, used as is in the next step.

Step 3: 1-(bromomethyl)-3-methylcyclobutane

To a solution of lithium bromide (1229 mg, 14.2 mmol) in acetone (8.0 mL) was added (3-methylcyclobutyl)methyl 4-methylbenzenesulfonate (450 mg, 1.8 mmol). The reaction mixture was heated at 70° C. for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude 1-(bromomethyl)-3-methylcyclobutane (288 mg, 80%) as colorless oil, used as is in the next step.

Step 4: 1-[(3-methylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (45 mg, 0.16 mmol), potassium carbonate (65 mg, 0.47 mmol) and 1-(bromomethyl)-3-methylcyclobutane (51 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (22-52% acetonitrile in water and 0.05% ammonia hydroxide) to give 1-[(3-methylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (11.1 mg, 19%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 6.12 (s, 1H), 4.56-4.52 (m, 1H), 4.34-4.22 (m, 5H), 3.33 (s, 3H), 2.89-2.64 (m, 2H), 2.27-2.20 (m, 7H), 1.41-1.39 (m, 1H), 1.13-1.02 (m, 3H). LCMS R_(T)=0.942 min, m/z=372.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.942 min, ESI+ found [M+H]=372.3.

Example 492 WX Method 010

N—(S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1S,3R)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: (3-(trifluoromethyl)cyclobutyl)methanol

To a solution of 3-(trifluoromethyl)cyclobutanecarboxylic acid (520 mg, 3.09 mmol) in tetrahydrofuran (15 mL) was added LiAlH₄ (235 mg, 6.19 mmol) at 0° C. After addition, the reaction mixture was stirred at 0° C. for 2 h and then quenched by addition of water (0.2 mL), 15% aqueous NaOH (0.2 mL) and water (0.6 mL). The mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (3-(trifluoromethyl)cyclobutyl)methanol (476 mg, 99%) as a colorless oil, used as is in the next step.

Step 2: (3-(trifluoromethyl)cyclobutyl)methyl 4-methylbenzenesulfonate

To a solution of (3-(trifluoromethyl)cyclobutyl)methanol (476 mg, 3.1 mmol) in dichloromethane (20 mL) was added 4-dimethylaminopyridine (755 mg, 6.2 mmol) and p-toluenesulfonylchloride (707 mg, 3.7 mmol). The reaction mixture was stirred at 20° C. for 12 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to afford (3-(trifluoromethyl)cyclobutyl)methyl 4-methylbenzenesulfonate (700 mg, 74%) as a colorless oil, used as is in the next step.

Step 3: methyl 1-(((1R,3R)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylate & methyl 1-(((1S,3S)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (289 mg, 2.3 mmol) and (3-(trifluoromethyl)cyclobutyl)methyl 4-methylbenzenesulfonate (700 mg, 2.27 mmol) in N,N-dimethylformamide (20 mL) was added 4-dimethylaminopyridine (333 mg, 2.7 mmol), cesium carbonate (2219 mg, 6.8 mmol) and sodium iodide (408 mg, 2.7 mmol). The mixture was stirred at 95° C. for 12 h and diluted with water (30 mL). The resulting solution was extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with water (3×20 mL), brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: 100-200 mesh, 0-90% ethyl acetate in petroleum ether) to afford methyl 1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylate (320 mg, 54%) as a colorless oil. This material was further separated by SFC to give: methyl 1-(((1R,3R)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylate (Peak 1, Retention time=4.723 min) (140 mg, 43.4%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.31-4.22 (m, 4H), 3.33 (s, 3H), 3.01-2.83 (m, 3H), 2.28-2.24 (m, 6H), 2.01-1.98 (m, 2H)

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.730 min, ESI+ found [M+H]=263.9.

methyl 1-(((1 S,3 S)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylate (Peak 2, Retention time=5.664 min) (140 mg, 43.4%) as white solids. ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 4.27 (d, J=7.6 Hz, 2H), 4.01 (s, 1H), 2.94-2.88 (m, 2H), 2.33-2.30 (m, 2H), 2.01-1.84 (m, 2H).

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.730 min, ESI+ found [M+H]=263.9.

SFC condition: Column: Chiralcel IC-3 150×4.6 mm I.D., 3 um Mobile phase: 40% iso-propanol (0.05% DEA) in CO₂ Flow rate: 2.5 mL/min Column temperature:40° C. SFC condition: column: chiralcel OD-3 100×4.6 mm I.D., 3 um mobile phase: A:CO₂; B: ethanol (0.05% DEA) gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Step 4: 1-(((1S,3S)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-(((1 S,3 S)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylate (140 mg, 0.53 mmol) and lithium hydroxide hydrate (112 mg, 2.66 mmol) in tetrahydrofuran/Methanol/Water (5 mL, 2:2:1) was stirred at 25° C. for 1 h. The solution was diluted with water (10 mL) and adjusted to pH=4-5 with addition of 1M HCl. The resulting solid was collected by filtration and dried under reduced pressure to give 1-(((1 S,3 S)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid (100 mg, 76%) as a white solid, used as is in the next step.

Step 5: N—(S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1 S,3R)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-(((1 S,3 S)-3-(trifluoromethyl)cyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid (31 mg, 0.12 mmol), 1-hydroxybenzotriazole (25 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (36 mg, 0.19 mmol) and (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (24 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonium hydroxide in water) to afford N—(S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1 S,3R)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (35.7 mg, 68%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.50 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.31-4.22 (m, 4H), 3.33 (s, 3H), 3.01-2.83 (m, 3H), 2.28-2.24 (m, 6H), 2.01-1.98 (m, 2H). LC-MS R_(T)=0.927 min, m/z=426.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.927 min, ESI+ found [M+H]=426.3.

Example 493

N—(S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1S,3R)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 010. The crude was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonium hydroxide in water) to give N—(S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1 S,3R)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (37.9 mg, 68%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 7.53 (s, 1H), 6.31 (d, J=2.0 Hz, 1H), 4.55-4.41 (m, 2H), 4.31-4.29 (m, 3H), 3.37 (s, 3H), 3.01-2.85 (m, 3H), 2.30-2.25 (m, 3H), 2.01-1.94 (m, 2H). LC-MS R_(T)=0.891 min, m/z=412.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.891 min, ESI+ found [M+H]=412.3.

Example 494

N—(S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1R,3S)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 011. The crude was purified by RP-HPLC (acetonitrile 46-76%/0.05% ammonium hydroxide in water) to give N—(S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(((1R,3 S)-3-trifluoromethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (25.4 mg, 45%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.51 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 6.31 (d, J=2.0 Hz, 1H), 4.52-4.29 (m, 5H), 3.37 (s, 3H), 3.07-2.88 (m, 3H), 2.33-2.26 (m, 3H), 2.18-2.14 (m, 2H). LC-MS R_(T)=0.903 min, m/z=412.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.903 min, ESI+ found [M+H]=412.3.

Example 495 WX Method 014

1-[(1-methylcyclopentyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1, 5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl cyclopentanecarboxylate

To a solution of cyclopentanecarboxylic acid (5.0 g, 43.8 mmol) in dichloromethane (30 mL) and methanol (10 mL) was added (trimethylsilyl)diazomethane (2.0 M in hexane, 109 mL, 219.0 mmol) at 25° C. After addition, the solution was stirred at 25° C. for 2 h and then concentrated under reduced pressure to give methyl cyclopentanecarboxylate (5 g, 89%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.67 (s, 3H), 2.77-2.71 (m, 1H), 1.90-1.87 (m, 2H), 1.81-1.70 (m, 4H), 1.59-1.57 (m, 2H).

Step 2: methyl 1-methylcyclopentanecarboxylate

To a solution of diisopropylamine (7.9 g, 78.0 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M in hexane, 31.2 mL, 78.0 mmol,) at −70° C. The mixture was stirred at −70° C. for 0.5 h, then methyl cyclopentanecarboxylate (5.0 g, 39.0 mmol) was added. After addition, stirring at −70° C. was continued for another 0.5 h, methyl iodide (7.3 mL, 117.0 mmol) was added. The resulting mixture was stirred at 20° C. for 12 h and quenched by addition of saturated aqueous ammonium chloride (100 mL). The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude methyl 1-methylcyclopentanecarboxylate (5.5 g, 99%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.67 (s, 3H), 2.11-2.05 (m, 2H), 1.69-1.66 (m, 4H), 1.48-1.45 (m, 2H), 1.24 (s, 3H)

Step 3: (1-methylcyclopentyl)methanol

To a solution of methyl 1-methylcyclopentanecarboxylate (1.0 g, 7.03 mmol) in tetrahydrofuran (15 mL) was added LiAlH₄ (533 mg, 14.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched by addition of water (0.5 mL), 15% aqueous NaOH (0.5 mL) and water (1.5 mL). The mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give (1-methylcyclopentyl)methanol (400 mg, 50%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 3.39 (s, 2H), 1.67-1.62 (m, 4H), 1.50-1.47 (m, 2H), 1.32-1.30 (m, 2H), 1.02 (s, 3H).

Step 4: (1-methylcyclopentyl)methyl 4-methylbenzenesulfonate

To a solution of (1-methylcyclopentyl) methanol (100 mg, 0.88 mmol) in dichloromethane (6 mL) was added 4-dimethylaminopyridine (214 mg, 1.75 mmol) and p-Toluenesulfonylchloride (200 mg, 1.05 mmol). The reaction mixture was stirred at 20° C. for 2 h and then quenched by addition of brine (6 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (10% ethyl acetate in petroleum ether, R_(f)=0.4) to afford (1-methylcyclopentyl)methyl 4-methylbenzene sulfonate (200 mg, 85%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 3.77 (s, 2H), 2.46 (s, 3H), 1.63-1.55 (m, 4H), 1.45-1.44 (m, 2H), 1.33-1.31 (m, 2H), 0.98 (s, 3H).

Step 5: methyl 1-((1-methylcyclopentyl)methyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (50 mg, 0.39 mmol) and (1-methylcyclopentyl)methyl 4-methylbenzenesulfonate (106 mg, 0.39 mmol) in N,N-dimethylformamide (4 mL) was added cesium carbonate (384 mg, 1.18 mmol), sodium iodide (71 mg, 0.47 mmol) and 4-dimethylaminopyridine (58 mg, 0.47 mmol). The mixture was stirred at 100° C. for 12 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and washed with water (2×10 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.5) to give methyl 1-[(1-methylcyclopentyl)methyl]-1,2,4-triazole-3-carboxylate (50 mg, 57%) as a colorless oil. LC-MS R_(T)=0.973 min, m/z=223.9 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.973 min, ESI+ found [M+H]=223.9.

Step 6: 1-((1-methylcyclopentyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(1-methylcyclopentyl)methyl]-1,2,4-triazole-3-carboxylate (50 mg, 0.22 mmol) and lithium hydroxide hydrate (47 mg, 1.12 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25° C. for 1 h. The solution was diluted with water (10 mL) and adjusted to pH=4-5 by addition of 1M HCl. The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 1-[(1-methylcyclopentyl)methyl]-1,2,4-triazole-3-carboxylic acid (45 mg, 96%) as a white solid. LC-MS R_(T)=1.055 min, m/z=209.9 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.055 min, ESI+ found [M+H]=209.9.

Step 7: 1-[(1-methylcyclopentyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1, 5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a stirred solution of 1-[(1-methylcyclopentyl)methyl]-1,2,4-triazole-3-carboxylic acid (32 mg, 0.15 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroxybenzotriazole (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (44 mg, 0.23 mmol) and (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.15 mmol). The resulting mixture was stirred at 25° C. for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to afford 1-[(1-methylcyclopentyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (26.4 mg, 44%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.31-4.22 (m, 2H), 4.18 (s, 2H), 3.34 (s, 3H), 2.90-2.83 (m, 1H), 2.30-2.23 (m, 4H), 1.71-1.65 (m, 6H), 1.39-1.36 (m, 2H), 0.97 (s, 3H). LC-MS R_(T)=0.677 min, m/z=386.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.677 min, ESI+ found [M+H]=386.2.

Examples 496 and 497 WX Method 015

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3R)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide and N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3S)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-[(3-methylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (120 mg, 0.94 mmol) and (3-methylcyclobutyl)methyl 4-methylbenzenesulfonate (240 mg, 0.94 mmol) in N,N-dimethylformamide (12 mL) was added 4-dimethylaminopyridine (138 mg, 1.13 mmol), cesium carbonate (923 mg, 2.83 mmol) and sodium iodide (170 mg, 1.13 mmol). The mixture was stirred at 95° C. for 12 h and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.2) to give methyl 1-[(3-methylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylate (70 mg, 35%) as a colorless oil.

LC-MS R_(T)=0.730 min, m/z=209.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.730 min ES+found M+H]=209.9.

Step 2: 1-((1-methylcyclopentyl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3-methylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylate (70 mg, 0.33 mmol) and lithium hydroxide hydrate (84 mg, 2.01 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25° C. for 1 h. The solution was diluted with water (10 mL) and adjusted to pH=4-5 by addition of 1M HCl. The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude 1-[(3-methylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid (60 mg, 92%) as a white solid. LC-MS R_(T)=0.377 min, m/z=195.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.377 min, ESI+ found [M+H]=195.9.

Step 3: N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3R)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide and N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3S)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a stirred solution of 1-[(3-methylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid (54 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (56 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (80 mg, 0.42 mmol) and (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.28 mmol). The mixture was stirred at 25° C. for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) to afford 1-[(3-methylcyclobutyl)methyl]-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (75 mg, 74%) as a white solid.

The racemic compound was further separated by chiral SFC to afford:

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1 S,3R)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 1, retention time=4.957 min) (43.8 mg, 58%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 6.31 (d, J=1.2 Hz, 1H), 4.54-4.40 (m, 2H), 4.43-4.41 (m, 1H), 4.23 (d, J=7.6 Hz, 2H), 3.36 (s, 3H), 2.88-2.83 (m, 1H), 2.68-2.64 (m, 1H), 2.31-2.17 (m, 4H), 1.44-1.36 (m, 2H), 1.03 (d, J=6.4 Hz, 3H). LC-MS R_(T)=0.649 min, m/z=358.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.649 min, ESI+ found [M+H]=358.2.

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3 S)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 2, Retention time=5.433 min) (22.7 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 6.31 (s, 1H), 4.54-4.49 (m, 2H), 4.34-4.29 (m, 3H), 3.36 (s, 3H), 2.87-2.82 (m, 2H), 2.49-2.40 (m, 1H), 2.29-2.20 (m, 1H), 2.01-1.94 (m, 2H), 1.76-1.71 (m, 2H), 1.12 (d, J=6.8 Hz, 3H). LC-MS R_(T)=0.649 min, m/z=358.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.649 min, ESI+ found [M+H]=358.2.

SFC condition: column chiralpak AD(250 mm*30 mm, 5 um), 3 um mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 35 to 35 of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Examples 498 and 499

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3R)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide and N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3S)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

The amide coupling prepared in a similar fashion to WX Method 015. The obtained racemic material (110 mg) was purified by chiral to give:

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3R)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 1, Retention time=3.887 min) (49.1 mg, 44%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 6.11 (s, 1H), 4.57-4.51 (m, 1H), 4.35-4.29 (m, 1H), 4.23-4.21 (m, 3H), 3.33 (s, 3H), 2.89-2.84 (m, 1H), 2.68-2.64 (m, 1H), 2.28-2.17 (m, 7H), 1.43-1.36 (m, 2H), 1.03 (d, J=6.4 Hz, 3H).

LC-MS R_(T)=1.531 min, m/z=372.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.531 min, ESI+ found [M+H]=372.1.

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3S)-3-methylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 2 Retention time=4.496 min) (22.8 mg, 21%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.48 (s, 1H), 6.11 (s, 1H), 4.56-4.51 (m, 1H), 4.34-4.29 (m, 3H), 4.24-4.22 (m, 1H), 3.33 (s, 3H), 2.89-2.83 (m, 2H), 2.45-2.43 (m, 1H), 2.25-2.19 (m, 4H), 2.01-1.94 (m, 2H), 1.76-1.69 (m, 2H), 1.12 (d, J=6.4 Hz, 3H). LC-MS R_(T)=1.531 min, m/z=372.0 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.531 min, ESI+ found [M+H]=372.0.

SFC condition: column: chiralpak AD-3 (100×4.6 mm), 3 um mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 5 to 40 of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Examples 500 and 501 WX Method 017

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3R)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide and N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3S)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Step 1: (3-ethylcyclobutyl)methanol

To a solution of 3-ethylcyclobutanecarboxylic acid (600 mg, 4.68 mmol) in tetrahydrofuran (10 mL) was added LiAlH₄ (355 mg, 9.36 mmol) at 0° C. After addition, the mixture was stirred at 25° C. for 16 h and quenched by addition of water (0.1 mL), 15% aqueous NaOH (0.1 mL) and water (0.3 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude (3-ethylcyclobutyl)methanol (535 mg, 110%) as a colorless oil, used as is in the next step, used as is in the next step.

Step 2: (3,3-dimethylcyclobutyl)methyl 4-methylbenzenesulfonate

To a solution of p-toluenesulfonylchloride (1071 mg, 5.62 mmol) in dichloromethane (10 mL) was added (3-ethylcyclobutyl)methanol (535 mg, 4.69 mmol) and 4-dimethylaminopyridine (1144 mg, 9.37 mmol). The reaction mixture was stirred at 20° C. for 16 h. Then the mixture was extracted with ethyl acetate (3×20 mL). The organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford (3-ethylcyclobutyl)methyl 4-methylbenzenesulfonate (810 mg, 64%) as a colorless oil, used as is in the next step.

Step 3: methyl 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (383 mg, 3.02 mmol) and (3-ethylcyclobutyl)methyl 4-methylbenzenesulfonate (810 mg, 3.02 mmol) in N,N-dimethylformamide (20 mL) was added 4-dimethylaminopyridine (442 mg, 3.62 mmol), cesium carbonate (2.95 g, 9.05 mmol) and sodium iodide (543 mg, 3.62 mmol). The mixture was stirred at 95° C. for 12 h and quenched by addition of water (30 mL). The mixture was extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with water (3×20 mL), brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: 100-200 mesh, 0-90% ethyl acetate in petroleum ether) to afford methyl 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylate (220 mg, 33%) as a colorless oil, used as is in the next step.

Step 4: 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylate (100 mg, 0.45 mmol) and lithium hydroxide hydrate (94 mg, 2.24 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25° C. for 2 h. The solvent was evaporated under reduced pressure. The residue was diluted with water (20 mL) and adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried to give 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid (74 mg, 79%) as a white solid, used as is in the next step.

Step 5 N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3R)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide and N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3S)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

To a stirred solution of (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (60 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was added 1-[(3-ethylcyclobutyl)methyl]-1,2,4-triazole-3-carboxylic acid (71 mg, 0.34 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (89 mg, 0.46 mmol). The mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 33-53%/0.05% ammonium hydroxide in water) to afford the racemic compound which was separated by SFC to afford: N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3R)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.975 min) (27 mg, 23%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 6.12 (s, 1H), 4.56-4.52 (m, 1H), 4.31-4.22 (m, 4H), 3.33 (s, 3H), 2.88-2.83 (m, 1H), 2.72-2.68 (m, 1H), 2.26-2.18 (m, 4H), 2.17-2.09 (m, 4H), 1.39-1.37 (m, 2H), 0.82-0.78 (m, 3H). LC-MS R_(T)=0.804 min, m/z=386.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.804 min, ESI+ found [M+H]=386.1.

N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3 S)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.253 min) (6 mg, 5%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.49 (s, 1H), 6.12 (s, 1H), 4.56-4.52 (m, 1H), 4.35-4.22 (m, 4H), 3.33 (s, 3H), 2.86-2.82 (m, 2H), 2.26-2.23 (m, 4H), 1.95-1.91 (m, 2H), 1.80-1.76 (m, 2H), 1.49-1.46 (m, 2H), 0.85-0.80 (m, 3H).

LC-MS R_(T)=0.806 min, m/z=386.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.806 min, ESI+ found [M+H]=386.1

SFC condition: Column: Chiralcel AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% dethyl acetate), Gradient: from 5% to 40% of B in 5.0 min and hold 40% for 2.5 min, then 5% of B for 2.5 min, Flow rate: 2.5 mL/min Column temperature:35° C.

Examples 502 and 503

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3R)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide and N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1S,3 S)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 017. The crude was purified by RP-HPLC (acetonitrile 22 to 52%/0.05% ammonium hydroxide in water) to give N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-((3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (75 mg, 61%) as a white solid. This material was separated by chiral SFC to give:

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1R,3R)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 1, retention time=5.49 min) (25 mg, 67%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 7.52 (s, 1H), 6.30 (s, 1H), 4.54-4.38 (m, 2H), 4.33-4.25 (m, 1H), 4.22 (d, J=7.2 Hz, 2H), 3.35 (s, 3H), 2.89-2.87 (m, 1H), 2.67-2.64 (m, 1H), 2.28-2.25 (m, 1H), 2.16-2.07 (m, 3H), 1.42-1.34 (m, 4H), 0.79 (t, J=7.2 Hz, 1H). LCMS R_(T)=1.62 min, m/z=372.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.62 min, ESI+ found [M+H]=372.2.

N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-(((1 S,3 S)-3-ethylcyclobutyl)methyl)-1H-1,2,4-triazole-3-carboxamide (Peak 2, Retention time=5.78 min) (26 mg, 67%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 7.52 (s, 1H), 6.30 (s, 1H), 4.53-4.51 (m, 1H), 4.42-4.39 (m, 1H), 4.34-4.27 (m, 3H), 3.35 (s, 3H), 2.89-2.81 (m, 2H), 2.27-2.22 (m, 2H), 1.92-1.89 (m, 2H), 1.79-1.75 (m, 2H), 1.48-1.44 (m, 2H), 0.82 (t, J=7.2 Hz, 1H). LCMS R_(T)=1.62 min, m/z=372.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.62 min, ESI+ found [M+H]=372.2.

SFC conditions: Column: Chiralcel AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: methanol (0.05% ethyl acetate), Gradient: from 5% to 40% of B in 5.0 min and hold 40% for 2.5 min, then 5% of B for 2.5 min, Flow rate: 2.5 mL/min Column temperature: 35° C.

Example 504 WX Method 100

1-[(2,5-difluorophenyl)methyl]-N-(3R)-1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

A mixture of 1-[(2,5-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (74 mg, 0.31 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (59 mg, 0.31 mmol), 1-hydroxybenzotriazole (42 mg, 0.31 mmol) and 3-amino-1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (50 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (5% to 35% acetonitrile/0.05% ammonia hydroxide in water) to afford 1-[(2,5-difluorophenyl)methyl]-N-(1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]di azepin-3-yl)-1,2,4-triazole-3-carboxamide (70 mg, 66%) as a white solid. The obtained racemic compound was separated by chiral SFC to give:

1-[(2,5-difluorophenyl)methyl]-N-(3R)-1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 3.664 min) (30 mg, 42%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.65 (s, 1H), 8.04 (s, 1H), 7.21-7.14 (m, 3H), 5.56 (s, 2H), 4.63-4.58 (m, 1H), 4.47-4.41 (m, 1H), 4.07-4.03 (m, 1H), 3.32 (s, 3H), 2.73-2.65 (m, 1H), 2.27 (s, 3H), 2.22-2.16 (m, 1H). LCMS R_(T)=0.557 min; m/z=416.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.557 min, ESI+ found [M+H]=416.0.

SFC conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um, Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 505

1-benzyl-N-(3R)-1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1, 2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 100. The racemic material was separated by chiral SFC to give:

1-benzyl-N-[(3R)-1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2, 4-triazole-3-carboxamide (Peak 2, retention time 3.944 min) (57.7 mg, 29%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ8.58 (s, 1H), 7.78 (s, 1H), 7.39-7.32 (m, 4H), 5.47 (s, 2H), 4.59-4.54 (m, 1H), 4.41-4.35 (m, 1H), 4.01-3.94 (m, 1H), 3.31 (s, 3H), 2.72-2.66 (m, 1H), 2.24 (s, 3H), 2.15-2.10 (m, 1H). LCMS R_(T)=0.508 min; m/z=380.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.508 min, ESI+ found [M+H]=380.0

SFC conditions: Column: Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.8 mL/min Column temp.: 40° C.).

Example 506

1-[(2,5-difluorophenyl)methyl]-N-[(7S)-9-methyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 100. The racemic material was separated by chiral SFC to give:

1-[(2,5-difluorophenyl)methyl]-N-[(7S)-9-methyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 3.766 min) (15 mg, 18.6%): ¹H NMR (400 MHz, CD₃OD) δ8.61 (s, 1H), 7.19-7.10 (m, 3H), 7.09 (s, 1H), 6.95 (s, 1H), 5.53 (s, 2H), 4.54-4.47 (m, 1H), 4.32-4.25 (m, 1H), 4.09-4.02 (m, 1H), 3.38 (s, 3H), 2.87-2.79 (m, 1H), 2.30-2.24 (m, 1H). LCMS R_(T)=1.324 min; m/z=402.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.324, ESI+ found [M+H]=402.2.

SFC conditions: Column: Chiralcel OJ-3 250×30 mm I.D., 10 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 30% to 30%, Flow rate: 80 mL/min, Column temp.: 40° C.

Example 507

1-[(2,5-difluorophenyl)methyl]-N-[(3R)-1-methyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 100. The racemic material was separated by chiral SFC to give:

1-[(2,5-difluorophenyl)methyl]-N-[(3R)-1-methyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.162 min) (33.8 mg 33%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.49 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.39-7.18 (m, 3H), 6.96 (s, 1H), 5.54 (s, 2H), 4.43-4.30 (m, 2H), 3.87-3.78 (m, 1H), 3.23 (s, 3H), 2.44 (s, 1H), 2.28-2.22 (m, 1H). LCMS R_(T)=1.716 min; m/z=402.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.716 min, ESI+ found [M+H]=402.2.

SFC conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 508 WX Method 162

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydrofuran]-2-carboxamide

Step 1: 2′-chloro-4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidin]-5′-one

To a solution of 2,2,6,6-tetramethylpiperidine (13.36 g, 94.6 mmol) in tetrahydrofuran (60 mL) was added n-butyllithium (2.5 M in hexanes, 50.5 mL, 126.2 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 2-chloropyrimidine-5-carboxylic acid (5.0 g, 31.5 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and dihydrofuran-3(2H)-one (10.61 g, 126.2 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, eluting 0-30% ethyl acetate in petroleum ether) to afford 2′-chloro-4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidin]-5′-one (700 mg, 10%) as yellow oil, used as is in the next step.

Step 2: 2′-chloro-4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidin]-5′-ol

To a solution of 2′-chloro-4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidin]-5′-one (700 mg, 3.09 mmol) in toluene (35 mL) was added diisobutylaluminumhydride (7.67 mL, 7.67 mmol, 1.0 M in toluene) at −78° C. The mixture was stirred at −78° C. for 2 h and quenched by addition of saturated ammonium chloride (15 mL). The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 2′-chloro-4,5-dihydro-2H,5′H-spiro [furan-3,7′-furo[3,4-d]pyrimidin]-5′-ol (250 mg, 35%) as light yellow oil, used as is in the next step.

Step 3: 2′-chloro-4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]

A mixture of 2′-chloro-4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidin]-5′-ol (250 mg, 1.1 mmol) and trifluoroacetic acid (0.41 mL, 5.5 mmol) in dichloromethane (20 mL) was added triethylsilane (0.87 mL, 5.5 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 2′-chloro-4,5-dihydro-2H, 5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine] (190 mg, 81%) as a yellow oil, used as is in the next step.

Step 4: 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carbonitrile

To a solution of 2′-chloro-4,5-dihydro-2H, 5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine] (190 mg, 0.89 mmol) in dimethyl sulfoxide (10 mL) and water (2 mL) was added 1,4-diazabicyclo[2.2.2]octane (20 mg, 0.18 mmol) and sodium cyanide (189 mg, 3.87 mmol). The reaction mixture was stirred at 25° C. for 7 h and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carbonitrile (120 mg, 66%) as a colourless oil.

Step 5: methyl 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carboxylate

To a solution of 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carbonitrile (120 mg, 0.59 mmol) in methanol (5 mL) was added HCl (4N in methanol, 2.4 mL). The reaction mixture was stirred at 25° C. for 15 h and concentrated under reduced pressure to afford crude methyl 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carboxylate (130 mg, 93%) as a white solid, used as is in the next step.

Step 6: 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carboxylic acid

A mixture of methyl 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carboxylate (130 mg, 0.55 mmol) and lithium hydroxide hydrate (132 mg, 5.50 mmol) in tetrahydrofuran (12 mL) and water (3 mL) was stirred at 25° C. for 2 h. The mixture was quenched by addition of 1N HCl (3 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 4,5-dihydro-2H,5′H-spiro[furan-3,7′-furo[3,4-d]pyrimidine]-2′-carboxylic acid (100 mg, 82%) as a yellow solid, used as is in the next step.

Step 7: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydrofuran]-2-carboxamide

A mixture of spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydrofuran]-2-carboxylic acid (69 mg, 0.31 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (60 mg, 0.31 mmol) and 1-hydroxybenzotriazole (42 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (24% to 54% acetonitrile/0.05% ammonia hydroxide in water) to give N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydrofuran]-2-carboxamide (41 mg, 40%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.85 (s, 1H), 7.46-7.44 (m, 1H), 7.36-7.29 (m, 2H), 7.27-7.24 (m, 1H), 5.19 (s, 2H), 5.08-5.03 (m, 1H), 4.68-4.64 (m, 1H), 4.49-4.43 (m, 1H), 4.17-4.02 (m, 4H), 3.43 (s, 3H), 2.49-2.40 (m, 1H), 2.34-2.29 (m, 1H). LC-MS R_(T)=0.891 min, m/z=397.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.891 min, ESI+ found [M+H]=397.1.

Example 509 WX Method 175

4-(1-hydroxycyclopentyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide

Step 1: 1-(2-bromopyrimidin-4-yl)cyclopentanol

To a solution of 2-bromo-4-iodo-pyrimidine (500 mg, 1.8 mmol) and cyclopentanone (221 mg, 2.6 mmol) in tetrahydrofuran (15 mL) was added isopropylmagnesium chloride (1.0 M in tetrahedron, 2.0 mL, 2.0 mmol) at −70° C. The mixture was stirred at −70° C. for 1 h and quenched by addition of saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (3×20 mL), brine (2×20 mL), dried over sodium sulfate and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25% ethyl acetate in petroleum ether) to afford 1-(2-bromopyrimidin-4-yl)cyclopentanol (80 mg, 19%) as colorless oil. ¹H NMR (400 MHz, CD₃OD) δ8.55 (d, J=5.0 Hz, 1H), 7.76 (d, J=5.3 Hz, 1H), 2.21-2.13 (m, 2H), 2.00-1.83 (m, 6H).

Step 2: 4-(1-hydroxycyclopentyl)pyrimidine-2-carbonitrile

To a solution of 1-(2-bromopyrimidin-4-yl)cyclopentanol (40 mg, 0.16 mmol) in dimethylsulfoxide (2 mL) and water (1 mL) was added 1,4-diazabicyclo[2.2.2]octane (18 mg, 0.16 mmol) and sodium cyanide (16 mg, 0.33 mmol). The mixture was stirred at 25° C. for 16 h and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 4-(1-hydroxycyclopentyl)pyrimidine-2-carbonitrile (30 mg, 96%) as yellow oil. ¹H NMR (400 MHz, CD₃OD) δ8.84 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 2.19-2.17 (m, 2H), 1.99-1.87 (m, 6H).

Step 3: methyl 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylate

To a solution of 4-(1-hydroxycyclopentyl)pyrimidine-2-carbonitrile (25 mg, 0.13 mmol) in methanol (5 mL) was added HCl (4N in methanol, 1.5 mL). The mixture was stirred at 25° C. for 20 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.3) to give methyl 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylate (15 mg, 51%) as colorless oil. ¹H NMR (400 MHz, CD₃OD) δ8.86 (d, J=5.6 Hz, 1H), 7.94 (d, J=5.6 Hz, 1H), 4.00 (s, 3H), 2.27-2.23 (m, 2H), 1.98-1.86 (m, 6H). LCMS R_(T)=0.523 min, m/z=223.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.523 min, ESI+ found [M+H]=223.0.

Step 4: 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylic acid

A mixture of methyl 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylate (15 mg, 0.07 mmol) and lithium hydroxide hydrate (14 mg, 0.34 mmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) was stirred at 25° C. for 16 h. The solution was adjusted to pH=4-5 by addition of 1N HCl. The mixture was concentrated under reduced pressure to give crude 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylic acid (11 mg, 78%) as a yellow solid.

LCMS R_(T)=0.290 min, m/z=208.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.290 min, ESI+ found [M+H]=208.9.

Step 5: 4-(1-hydroxycyclopentyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (10 mg, 0.05 mmol), 4-(1-hydroxycyclopentyl)pyrimidine-2-carboxylicacid (10 mg, 0.05 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (8 mg, 0.06 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (11 mg, 0.06 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25% to 55%/0.05% ammonia hydroxide in water) to give 4-(1-hydroxycyclopentyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide (10.3 mg, 56%) as a white solid. ¹H NMR (400 MHz, CD3OD) δ 8.87 (d, J=5.2 Hz, 1H), 7.90 (d, J=4.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.36-7.29 (m, 2H), 7.28-7.23 (m, 1H), 5.05-5.00 (m, 1H), 4.71-4.67 (m, 1H), 4.44-4.39 (m, 1H), 3.44 (s, 3H), 2.28-2.24 (m, 2H), 2.03-1.96 (m, 6H). LC-MS R_(T)=0.664 min, m/z=383.1 [M+H]⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 2.023 min, ESI+ found [M+H]=383.1.

Example 510 WX Method 160

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide

Step 1: 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-5-one

To a solution of 2,2,6,6-tetramethylpiperidine (13.36 g, 94.6 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M in hexanes, 25.2 mL, 63.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 2-chloropyrimidine-5-carboxylic acid (5.0 g, 31.5 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and dihydro-2H-pyran-4(3H)-one (9.47 g, 94.6 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-5-one (1.5 g, 20%) as a yellow solid.

Step 2: 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-5-ol

To a solution of 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-5-one (100 mg, 0.42 mmol) in tetrahydrofuran (3 mL) was added diisobutylaluminumhydride (1.66 mL, 1.66 mmol, 1.0 M in toluene). The reaction mixture was stirred at −70° C. for 2 h and quenched by addition of saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, Rf=0.3) to afford 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-5-ol (50 mg, 50%) as a colourless oil.

Step 3: 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]

To a solution of 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-5-ol (50 mg, 0.21 mmol) and trifluoroacetic acid (0.4 g, 3.53 mmol) in dichloromethane (5 mL) was added triethylsilane (118 mg, 1.03 mmol) at 0° C. After addition, the mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by preparative TLC (33% ethyl acetate in petroleum ether, Rf=0.4) to afford 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran] (30 mg, 64%) as a light yellow solid.

Step 4: 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carbonitrile

To a solution of 2-chloro-2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran] (30 mg, 0.13 mmol) in dimethyl sulfoxide (4 mL) and water (2 mL) was added 1,4-diazabicyclo[2.2.2]octane (8 mg, 0.07 mmol) and sodium cyanide (21 mg, 0.43 mmol). The reaction mixture was stirred at 25° C. for 12 h and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carbonitrile (20 mg, 70%) as a light yellow solid.

Step 5: methyl 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carboxylate

To a solution of 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carbonitrile (20 mg, 0.09 mmol) in methanol (1.5 mL) and was added HCl (4N in methanol, 0.5 mL). The reaction mixture was stirred at 25° C. for 2 h and 35° C. for 15 h. The mixture was concentrated under reduced pressure to afford crude methyl 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carboxylate (15 mg, 65%) as a yellow solid.

Step 6: 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carboxylic acid

A mixture of methyl 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carboxylate (15 mg, 0.06 mmol) and lithium hydroxide hydrate (7 mg, 0.30 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL) was stirred at 25° C. for 16 h. The mixture was quenched by addition of 1N HCl (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 2′,3′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4′-pyran]-2-carboxylic acid (10 mg, 70%) as a white solid.

Step 7: N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (9 mg, 0.05 mmol), 1-hydroxybenzotriazole (7 mg, 0.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (9 mg, 0.05 mmol), and spiro[5H-furo[3,4-d]pyrimidine-7,4′-tetrahydropyran]-2-carboxylic acid (10 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was stirred at 25° C. for 16 h. The mixture was concentrate under reduced pressure and the residue was purified by RP-HPLC (25% to 55% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo [3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide (4 mg, 21%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.85 (s, 1H), 7.46-7.44 (m, 1H), 7.35-7.31 (m, 2H), 7.26-7.25 (m, 1H), 5.19 (s, 2H), 5.07-5.03 (m, 1H), 4.71-4.68 (m, 1H), 4.66-4.42 (m, 1H), 3.99-3.97 (m, 2H), 3.87-3.82 (m, 2H), 3.44 (s, 3H), 2.24-2.21 (m, 2H), 1.70-1.67 (m, 2H). LC-MS R_(T)=1.923 min, m/z=411.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.923 min, ESI+ found [M+H]=411.1.

Example 511

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 160. The crude was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide (21 mg, 19.2% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 1H), 7.46-7.44 (m, 1H), 7.36-7.30 (m, 2H), 7.27-7.24 (m, 1H), 5.22 (s, 2H), 5.07-5.03 (m, 1H), 4.70-4.66 (m, 1H), 4.47-4.42 (m, 1H), 3.97-3.94 (m, 1H), 3.82-3.74 (m, 2H), 3.69-3.61 (m, 1H), 3.44 (s, 3H), 2.22-2.15 (m, 1H), 2.10-2.01 (m, 1H), 1.94-1.89 (m, 1H), 1.78-1.72 (m, 1H). LCMS R_(T)=0.913 min, m/z=411.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.913 min, ESI+ found [M+H]=411.2.

Example 512

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,4′-tetrahydropyran]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 160. The crude was purified by RP-HPLC (8% to 38% acetonitrile, 0.05% ammonia hydroxide in water) to give N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo [3,4-d]pyrimidine-7,4′-tetrahydropyran]-2-carboxamide (18.1 mg, 33.8%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 1H), 6.14 (s, 1H), 5.20 (s, 2H), 4.88-4.57 (m, 1H), 4.33-4.26 (m, 2H), 3.98-3.88 (m, 2H), 3.85-3.82 (m, 2H), 3.36 (s, 3H), 2.96-2.91 (m, 1H), 2.30-2.21 (m, 6H), 1.69-1.66 (m, 2H). LC-MS R_(T)=1.052 min, m/z=413.0 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.052 min, ESI+ found [M+H]=413.0.

Example 513

5-[(2,3-difluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide and 5-[(2,3-difluorophenyl)methyl]-N-(6R)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 011. The crude was purified by RP-HPLC (acetonitrile 28-58%/0.05% ammonium hydroxide in water) to give 5-[(2,3-difluorophenyl)methyl]-N-(2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (170 mg, 79%) as a white solid. The racemic material was separated by chiral SFC to give:

5-[(2,3-difluorophenyl)methyl]-N-(6 S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 1, Retention time=3.977 min) (77 mg, 48%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.20-7.11 (m, 3H), 6.10 (s, 1H), 4.54-4.49 (m, 1H), 4.30-4.20 (m, 4H), 3.32 (s, 3H), 2.86-2.79 (m, 1H), 2.27-2.21 (m, 4H).

LC-MS R_(T)=0.637 min, m/z=416.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.637 min, ESI+ found [M+H]=416.1.

5-[(2,3-difluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 2, Retention time=4.582 min) (77.5 mg, 48%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.20-7.11 (m, 3H), 6.10 (s, 1H), 4.54-4.49 (m, 1H), 4.30-4.20 (m, 4H), 3.32 (s, 3H), 2.86-2.79 (m, 1H), 2.27-2.21 (m, 4H).

LC-MS R_(T)=0.637 min, m/z=416.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.637 min, ESI+ found [M+H]=416.1.

SFC condition: column: chiralpak OD-3 100×4.6 mm I.D., 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: from 30% to 30% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example 514

5-[(2,3-difluorophenyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide and 5-[(2,3-difluorophenyl)methyl]-N-(6R)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[

1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide Amide coupling prepared in a similar fashion to WX Method 011. The crude was purified by RP-HPLC (acetonitrile 28-58%/0.05% ammonium hydroxide in water) to give 5-[(2,3-difluorophenyl)methyl]-N-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1, 5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (100 mg, 49%) as a white solid. The racemic material was separated by chiral SFC to give:

5-[(2,3-difluorophenyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 1, Retention time=4.389 min) (42.7 mg, 42%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.26-7.07 (m, 3H), 6.01 (s, 1H), 4.53-4.50 (m, 1H), 4.33-4.16 (m, 4H), 3.35-3.32 (m, 3H), 2.85-2.79 (m, 1H), 2.26-2.22 (m, 1H), 1.92-1.98 (m, 1H), 0.98-0.89 (m, 2H), 0.77-0.69 (m, 2H). LC-MS R_(T)=0.704 min, m/z=442.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.704 min, ESI+ found [M+H]=442.1.

5-[(2,3-difluorophenyl)methyl]-N-(6R)-2-cyclopropyl-4-methyl-1-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 2, Retention time=4.804 min) (54.9 mg, 54%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.26-7.07 (m, 3H), 6.01 (s, 1H), 4.53-4.50 (m, 1H), 4.33-4.16 (m, 4H), 3.35-3.32 (m, 3H), 2.85-2.79 (m, 1H), 2.26-2.22 (m, 1H), 1.92-1.98 (m, 1H), 0.98-0.89 (m, 2H), 0.77-0.69 (m, 2H). LC-MS R_(T)=0.704 min, m/z=442.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.704 min, ESI+ found [M+H]=442.2.

SFC condition: column: chiralpak OD-3 100×4.6 mm I.D., 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: from 30% to 30% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Examples 515, 516 and 517 WX Method 121

8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1, 2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide and (8S)-8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide and (8R)-8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

Step 1: 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole

To a solution of 3,5-dibromo-1H-1,2,4-triazole (10 g, 44.1 mmol) in acetonitrile (100 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (8.0 mL, 52.9 mmol) and N,N-diisopropylethylamine (8.45 mL, 48.5 mmol). The mixture was stirred at 90° C. for 3 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL), washed saturated sodium bicarbonate (2×50 mL), brine (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (13 g, 83%) as a colorless oil, used as is in the next step.

Step 2: [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol

To a solution of 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2.0 g, 5.6 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h and then a solution of benzaldehyde (1.2 g, 11.3 mmol) in THF (2 mL) was added. After addition, the mixture was stirred at −78° C. for another 1 h and then quenched by addition of saturated ammonium chloride (10 mL). The resulting mixture was diluted with ethyl acetate (100 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol (1.5 g, 69.7%) as a light yellow oil, used as is in the next step.

Step 3: 2-bromo-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A mixture of [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol (1.5 g, 3.92 mmol) and p-toluenesulfonic acid (863 mg, 5.02 mmol) in toluene (50 mL) was heated at reflux for 5 h. After cooled, the reaction was diluted with ethyl acetate (100 mL), washed with sodium hydroxide (1N, 20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford 2-bromo-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine (800 mg, 73%) as a yellow oil. LCMS R_(T)=0.642 min, m/z=281.6 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.642 min, ESI+ found [M+H]=281.6

Step 4: methyl 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate

A mixture of 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (13 mg, 0.02 mmol), 2-bromo-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine (300 mg, 1.07 mmol) and triethylamine(1.45 mL, 10.7 mmol) in methanol (30 mL) was heated at 70° C. for 12 h under CO (40 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate (100 mg, 20%) as a brown oil.

LCMS R_(T)=0.682 min, m/z=259.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.682 min, ESI+ found [M+H]=259.9

Step 5: 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid

A mixture of methyl 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate (50 mg, 0.11 mmol) and lithium hydroxide (8 mg, 0.32 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was stirred at 25° C. for 1 h. The mixture was adjusted to pH=3 by addition of 2N HCl and extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated under reduced pressure to afford crude 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid (25 mg, 94% crude yield) as a yellow solid, used as is in the next step.

Step 6: 8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro 1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1, 2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide and (8S)-8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide and (8R)-8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochlororide (45 mg, 0.24 mmol), 1-hyroxybenzotriazole (30 mg, 0.23 mmol) and 8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid (25 mg, 0.10 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and the residue purified by RP-HPLC (28% to 58% acetonitrile/0.05% ammonia hydroxide in water) to give 8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (14.5 mg, 33.6%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.80 (s, 1H), 7.46-7.44 (m, 1H), 7.34-7.32 (m, 2H), 7.27-7.24 (m, 1H), 5.12 (s, 2H), 5.07-5.02 (m, 1H), 4.69-4.68 (m, 1H), 4.46-4.43 (m, 1H), 3.44 (s, 3H), 2.08-2.04 (m, 4H), 1.95-1.93 (m, 4H). LCMS R_(T)=1.009 min, m/z=420.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.009 min, ESI+ found [M+H]=420.2

Another Batch of Racemic Material was Separated (70 mg) by Chiral SFC to Give:

(8S)-8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 1, retention time: 4.182 min) (10.9 mg, 14%), as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ7.41-7.38 (m, 6H), 7.30-7.29 (m, 2H), 7.22-7.21 (m, 1H), 5.94 (s, 1H), 5.01-4.96 (m, 1H), 4.58-4.53 (m, 1H), 4.47-4.35 (m, 4H), 4.30-4.25 (m, 1H), 3.38 (s, 3H). LCMS R_(T)=0.809 min, m/z=420.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.809 min, ESI+ found [M+H]=420.0

(8R)-8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 2, retention time 5.374 min) (10 mg, 14%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ7.41-7.38 (m, 6H), 7.30-7.29 (m, 2H), 7.22-7.21 (m, 1H), 5.94 (s, 1H), 5.01-4.96 (m, 1H), 4.57-4.47 (m, 2H), 4.40-4.35 (m, 3H), 4.25-4.20 (m, 1H), 3.38 (s, 3H). LCMS R_(T)=0.809 min, m/z=420.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.809 min, ESI+ found [M+H]=420.0

SFC condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 518 WX Method 043

1-[(2-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.68 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (21.7 g, 157.36 mmol) and 2-fluorobenzyl bromide (17.9 g, 94.41 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was diluted with brine (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (5.0 g, 27% yield) as a white solid, used as is in the next step.

Step 2: 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (40.0 g, 170.00 mmol) and potassium hydroxide (19.1 g, 340.12 mmol) in ethanol (800 mL) and water (200 mL) was stirred at 25° C. for 12 h. The ethanol was concentrated under reduced pressure and the aqueous solution was adjusted to pH=4 by addition of 2 N HCl. The resulting solid was collected by filtration and dried to give 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (33.0 g, 87.7%) as a white solid, used as is in the next step.

Step 3: 1-[(2-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a stirred solution of 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (23.9 g, 108.12 mmol) in N,N-dimethylformamide (6 mL) was added (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20.0 g, 102.97 mmol), 1-hydroxybenzotriazole (2.78 g, 20.59 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (29.61 g, 154.46 mmol). The mixture was stirred at 20° C. for 2 h. The mixture was poured in to sat. brine, then white solid was formed. The cake was collected and washed with ethyl acetate. The solid was recrystallized in ethanol/water to give 1-[(2-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (29.1 g, 71%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.57 (s, 1H), 7.40-7.35 (m, 2H), 7.21-7.12 (m, 2H), 6.10 (s, 1H), 5.54 (s, 2H), 4.54-4.49 (m, 1H), 4.29-4.15 (m, 2H), 3.31 (s, 3H), 2.87-2.79 (m, 1H), 2.27-2.20 (m, 4H). LC-MS R_(T)=1.426 min, m/z=398.2 (M+H)⁺.

LCMS (10 to 80% ammonium hydroxide in water+0.03% trifluoacetic acid over 1.5 mins) retention time 1.426 min, ESI+ found [M+H]=398.2

Example 519

1-[(3-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 049. The crude was purification by RP-HPLC (acetonitrile 42-62%/0.05 ammonium hydroxide in water) to give 1-[(3-fluorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 1.663 min) (44 mg, 43%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.60 (s, 1H), 7.42-7.36 (m, 1H), 7.17-7.06 (m, 3H), 6.11 (s, 1H), 5.49 (s, 2H), 4.56-4.51 (m, 1H), 4.31-4.18 (m, 2H), 3.32 (d, J=5.2 Hz, 3H), 2.87-2.81 (m, 1H), 2.28-2.23 (m, 4H). LCMS R_(T)=0.904 min, m/z=398.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.904 min, ESI+ found [M+H]=398.2

Example 520 WX Method 073

1-[(2-chlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-[(2-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.68 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (21.8 g, 157.36 mmol) and 2-chlorobenzyl bromide (19.4 g, 94.41 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-[(2-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylate (5.0 g, 25%) as a white solid, used as is in the next step, used as is in the next step.

Step 2: 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(2-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylate (5.0 g, 19.87 mmol) and potassium hydroxide (2.2 g, 39.73 mmol) in ethanol (80 mL) and water (15 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The solution was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried under reduced pressure to obtain 1-[(2-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (3.0 g, 64%) as white solids. ¹H NMR (400 MHz, DMSO-d6) δ8.79 (s, 1H), 7.52-7.50 (m, 1H), 7.41-7.37 (m, 2H), 7.37-7.29 (m, 2H), 5.59 (s, 2H).

Step 3: 1-[(2-chlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (74 mg, 0.39 mmol), 1-hydroxybenzotriazole (52 mg, 0.39 mmol), 1-[(2-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (73 mg, 0.31 mmol) and (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 28-58%/0.05% ammonia hydroxide in water) to afford 1-[(2-chlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (34.6 mg, 32%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.57 (s, 1H), 7.46-7.36 (m, 1H), 7.35-7.32 (m, 3H), 6.10 (s, 1H), 5.60 (s, 2H), 4.54-4.49 (m, 1H), 4.33-4.19 (m, 2H), 3.30 (s, 3H), 2.85-2.79 (m, 1H), 2.27-2.21 (m, 4H). LCMS R_(T)=0.763 min, m/z=414.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.763 min, ESI+ found [M+H]=414.1

Example 521 WX Method 077

1-[(3-chlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.68 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (21.8 g, 157.36 mmol) and 3-chlorobenzyl bromide (19.4 g, 94.41 mmol). The mixture was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylate (3.0 g, 15%) as white solids, used as is in the next step.

Step 2: 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylate (3.0 g, 11.92 mmol) and potassium hydroxide (1.3 g, 23.84 mmol) in ethanol (80 mL) and water (15 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The solution was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried under reduced pressure to obtain 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (2.0 g, 71%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ8.80 (s, 1H), 7.42-7.38 (m, 3H), 7.29-7.26 (m, 1H), 5.50 (s, 2H).

Step 3: 1-[(3-chlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 1-hydroxybenzotriazole (52 mg, 0.39 mmol), 1-[(3-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (73 mg, 0.31 mmol), (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.26 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (74 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 28-58%/0.05% ammonia hydroxide in water) to afford 1-[(3-chlorophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (36.01 mg, 34%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 7.37-7.25 (m, 4H), 6.10 (s, 1H), 5.46 (s, 2H), 4.54-4.49 (m, 1H), 4.29-4.27 (m, 1H), 4.24-4.19 (m, 1H), 3.31-3.29 (m, 3H), 2.85-2.79 (m, 1H), 2.28-2.21 (s, 4H). LC-MS R_(T)=0.755 min, m/z=414.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.755 min, ESI+ found [M+H]=414.1

Example 522

1-[(2-chlorophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 073 The crude was purified by RP-HPLC (ACN 45-75%/0.05% ammonia hydroxide in water) to afford 1-[(2-chlorophenyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (31.5 mg, 30%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.45-7.30 (m, 4H), 5.98 (s, 1H), 5.59 (s, 2H), 4.52-4.47 (m, 1H), 4.29-4.17 (m, 2H), 3.30 (s, 3H), 2.83-2.78 (m, 1H), 2.24-2.21 (m, 1H), 1.90-1.87 (m, 1H), 0.93-0.90 (m, 2H), 0.73-0.70 (m, 2H). LCMS R_(T)=0.794 min, m/z=440.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.794 min, ESI+ found [M+H]=440.1.

Example 523 WX Method 066

1-[(2,3-difluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(2, 3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.68 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (21.8 g, 157.36 mmol) and 2,3-difluorobenzyl bromide (19.6 g, 94.41 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford crude methyl 1-(2,3-difluorobenzyl)-1H-1,2, 4-triazole-3-carboxylate (10.2 g, 51%) as white solids, used as is in the next step.

Step 2: 1-(2, 3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(2,3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (2.0 g, 7.9 mmol) and potassium hydroxide (0.9 g, 15.8 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25° C. for 12 h. The ethanol was evaporated and the residue was diluted with water (20 mL). The mixture was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried to give 1-(2, 3-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (1.6 g, 85%) as white solids. ¹H NMR (400 MHz, CD30OD) δ 8.68 (s, 1H), 7.31-7.28 (m, 1H), 7.20-7.18 (m, 2H), 5.61 (s, 2H).

Step 3: 1-[(2,3-difluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.20 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (39 mg, 0.20 mmol) and 1-[(2,3-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (48 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was stirred at 20° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to afford the racemic material ((80 mg, 85%), which was separated by chiral SFC to give:

1-[(2,3-difluorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time 5.327 min) (22.8 mg, 29%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.48-7.42 (m, 1H), 7.05-6.97 (m, 2H), 6.66 (s, 1H), 5.52 (s, 2H), 4.53-4.44 (m, 2H), 4.39-4.33 (m, 1H), 3.36 (s, 3H), 2.89-2.84 (m, 1H), 2.35-2.29 (m, 1H). LCMS R_(T)=0.812 min, m/z=470.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.812 min, ESI+ found [M+H]=470.1.

SFC conditions: Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 524

5-[(2,3-difluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide and 5-[(2,3-difluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 011. The crude was separated by chiral SFC to give:

5-[(2,3-difluorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 1, retention time: 2.787 min) (41 mg, 44%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.37-7.31 (m, 1H), 7.19-7.13 (m, 2H), 6.94 (s, 1H), 4.50-4.44 (m, 1H), 4.36-4.32 (m, 2H), 4.19 (s, 2H), 3.27 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.808 min, m/z=470.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.808 min, ESI+ found [M+H]=470.1

5-[(2,3-difluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 1, retention time: 3.099 min) (29 mg, 31%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 7.37-7.31 (m, 1H), 7.19-7.13 (m, 2H), 6.94 (s, 1H), 4.50-4.44 (m, 1H), 4.36-4.32 (m, 2H), 4.19 (s, 2H), 3.27 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.808 min, m/z=470.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.808 min, ESI+ found [M+H]=470.1.

SFC condition: Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 525 WX Method 067

1-[(4-fluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(4-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.68 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (21.8 g, 157.36 mmol) and 4-fluorobenzyl chloride (13.7 g, 94.41 mmol). The mixture was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford methyl 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylate (7.8 g, 42%) as white solids.

Step 2: 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (2.0 g, 8.5 mmol) and potassium hydroxide (954 mg, 17.0 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25° C. for 12 h. The ethanol was evaporated and the residue was diluted with water (20 mL). The mixture was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried to give 1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (1.5 g, 81%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.63 (s, 1H), 7.44-7.40 (m, 2H), 7.14-7.09 (m, 2H), 5.47 (s, 2H).

Step 3: 1-[(4-fluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(4-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a solution of 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole (33 mg, 0.24 mmol) and 1-[(4-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (53 mg, 0.24 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% ammonium hydroxide in water) to afford the racemic material which was separated by chiral SFC to give: 1-[(4-fluorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time 5.728 min) (35 mg, 37%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.21 (t, J=8.8 Hz, 2H), 6.94 (s, 1H), 5.47 (s, 2H), 4.48-4.44 (m, 1H), 4.37-4.30 (m, 2H), 3.27 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.810 min, m/z=452.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.810 min, ESI+ found [M+H]=452.1.

1-[(4-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 7.422 min) (33 mg, 36%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.21 (t, J=8.8 Hz, 2H), 6.94 (s, 1H), 5.47 (s, 2H), 4.48-4.44 (m, 1H), 4.37-4.30 (m, 2H), 3.27 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.806 min, m/z=452.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.806 min, ESI+ found [M+H]=452.1.

SFC condition: Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 526

1-[(2-fluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 043. The obtained racemic compound was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time=5.180 min) (24 mg, 25%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 7.43-7.33 (m, 2H), 7.26-7.20 (m, 2H), 6.94 (s, 1H), 5.55 (s, 2H), 4.49-4.44 (m, 1H), 4.36-4.30 (m, 2H), 3.26 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.803 min, m/z=452.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.803 min, ESI+ found [M+H]=452.1.

1-[(2-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time=5.97 min) (18 mg, 20%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 7.43-7.33 (m, 2H), 7.26-7.20 (m, 2H), 6.94 (s, 1H), 5.55 (s, 2H), 4.49-4.44 (m, 1H), 4.36-4.30 (m, 2H), 3.26 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.806 min, m/z=452.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.806 min, ESI+ found [M+H]=452.0.

SFC conditions: Column Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 527 WX Method 049

1-[(3-fluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(3-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.68 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (21.8 g, 157.36 mmol) and 3-fluorobenzyl bromide (17.9 g, 94.41 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was diluted with brine (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (5.0 g, 27%) as a white solid.

Step 2: 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (5.0 g, 21.26 mmol) and potassium hydroxide (2.4 g, 42.52 mmol) in ethanol (80 mL) and water (15 mL) was stirred at 25° C. for 12 h. The ethanol was evaporated under reduced pressure and the aqueous residue was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried to obtain crude 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (3.0 g, 64%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ8.81 (s, 1H), 7.47-7.35 (m, 1H), 7.23-7.09 (m, 2H), 5.51 (s, 2H).

Step 3: 1-[(3-fluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(3-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a solution of 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazole (27 mg, 0.20 mmol), 1-[(3-fluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (44 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (39 mg, 0.20 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.1% ammonia hydroxide in water) to afford 1-(3-fluorobenzyl)-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1, 5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (65 mg, 69%). The racemic material was separated by chiral SFC to give:

1-[(3-fluorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time 5.675 min) (28 mg, 30%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.68 (d, J=8.0 Hz, 1H), 7.46-7.40 (m, 1H), 7.19-7.12 (m, 3H), 6.94 (s, 1H), 5.51 (s, 2H), 4.50-4.44 (m, 1H), 4.37-4.31 (m, 2H), 3.27 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.807 min, m/z=452.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.807 min, ESI+ found [M+H]=452.0.

1-[(3-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 7.386 min) (29 mg, 31%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.68 (d, J=8.0 Hz, 1H), 7.46-7.40 (m, 1H), 7.19-7.12 (m, 3H), 6.94 (s, 1H), 5.51 (s, 2H), 4.50-4.44 (m, 1H), 4.37-4.31 (m, 2H), 3.27 (s, 3H), 2.64-2.60 (m, 1H), 2.52-2.48 (m, 1H). LCMS R_(T)=0.811 min, m/z=452.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.811 min, ESI+ found [M+H]=452.1.

SFC conditions: Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 528 WX Method 076

1-[(2-chlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-1-[(2-chlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 073 (RIP1K_experimental_3^(rd)_WX.doc). The obtained racemic compound was separated by chiral SFC:

1-[(2-chlorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time=4.393 min) (20 mg, 40%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.58 (s, 1H), 7.47-7.42 (m, 1H), 7.42-7.28 (m, 3H), 6.68 (s, 1H), 5.61 (s, 2H), 4.56-4.46 (m, 2H), 4.41-4.33 (m, 1H), 3.37 (s, 3H), 2.93-2.86 (m, 1H), 2.36-2.29 (m, 1H). LC-MS R_(T)=1.838 min, m/z=468.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.838 min, ESI+ found [M+H]=468.1. 1-1-[(2-chlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time=5.055 min) (21 mg, 41%) as white solids. ¹H NMR (400 MHz, METHANOL-d4) 68.58 (s, 1H), 7.47-7.42 (m, 1H), 7.42-7.28 (m, 3H), 6.68 (s, 1H), 5.61 (s, 2H), 4.56-4.46 (m, 2H), 4.41-4.33 (m, 1H), 3.37 (s, 3H), 2.93-2.86 (m, 1H), 2.36-2.29 (m, 1H). LC-MS R_(T)=1.838 min, m/z=468.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.838 min, ESI+ found [M+H]=468.1.

SFC condition: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 529 WX Method 065

1-[(2,4-difluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(2,4-difluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (10.0 g, 78.68 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (21.8 g, 157.36 mmol) and 2,4-difluorobenzyl bromide (19.6 g, 94.41 mmol). The mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was diluted with brine (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford methyl 1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylate (7.7 g, 38.6%) as white solids.

Step 2: 1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylate (2.0 g, 7.9 mmol). and potassium hydroxide (0.9 g, 15.8 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25° C. for 12 h. The ethanol was evaporated under reduced pressure and the residue was diluted with water (20 mL). The solution was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried to give crude 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (1.69 g, 90%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ8.64 (s, 1H), 7.51-7.47 (m, 1H), 7.06-7.00 (m, 2H), 5.54-5.49 (m, 2H).

Step 3: 1-[(2,4-difluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(2,4-difluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (42 mg, 0.22 mmol), 1-[(2,4-difluorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (55 mg, 0.23 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonium hydroxide in water) to afford 1-[(2,4-difluorophenyl)methyl]-N-[4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (50 mg, 53%) as white solid. The obtained racemic material was separated by chiral SFC to give:

1-[(2,4-difluorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time=3.802 min) (14 mg, 27%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.48-7.42 (m, 1H), 7.05-6.97 (m, 2H), 6.66 (s, 1H), 5.52 (s, 2H), 4.53-4.44 (m, 2H), 4.39-4.33 (m, 1H), 3.36 (s, 3H), 2.89-2.84 (m, 1H), 2.35-2.29 (m, 1H). LCMS R_(T)=1.805 min; m/z=470.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.805 min, ESI+ found [M+H]=470.1.

1-[(2,4-difluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time=4.620 min) (14 mg, 27% yield) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.59 (s, 1H), 7.50-7.42 (m, 1H), 7.08-6.94 (m, 2H), 6.68 (s, 1H), 5.53 (s, 2H), 4.57-4.47 (m, 2H), 4.41-4.33 (m, 1H), 3.37 (s, 3H), 2.92-2.84 (m, 1H), 2.35-2.29 (m, 1H). LCMS R_(T)=1.805 min; m/z=470.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.805 min, ESI+ found [M+H]=470.1.

SFC condition: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 530

1-[(2-fluorophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 043. The crude was purified by RP-HPLC (acetonitrile 42-62%/0.05% ammonium hydroxide in water) to give 1-[(2-fluorophenyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (38 mg, 33.6%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.58 (s, 1H), 7.41-7.36 (m, 2H), 7.21-7.15 (m, 2H), 6.00 (s, 1H), 5.55 (s, 2H), 4.53-4.48 (m, 1H), 4.32-4.21 (m, 2H), 3.31 (s, 3H), 2.86-2.79 (m, 1H), 2.25-2.23 (m, 1H), 1.91-1.87 (m, 1H), 0.95-0.92 (m, 2H), 0.75-0.72 (m, 2H). LC-MS R_(T)=0.958 min, m/z=424.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.958 min, ESI+ found [M+H]=424.2.

Example 531

1-[(3-fluorophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 049. The crude was purification by RP-HPLC (acetonitrile 17-47%/0.05 ammonium hydroxide in water) to give 1-[(3-fluorophenyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time 1.762 min) (28 mg, 25%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.61 (s, 1H), 7.40-7.36 (m, 1H), 7.17-7.08 (m, 3H), 6.00 (s, 1H), 5.49 (s, 2H), 4.55-4.50 (m, 1H), 4.31-4.19 (m, 2H), 3.31 (s, 3H), 2.87-2.80 (m, 1H), 2.28-2.24 (m, 1H), 1.91-1.88 (m, 1H), 0.95-0.92 (m, 2H), 0.75-0.73 (m, 2H). LCMS R_(T)=0.958 min, m/z=424.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.958 min, ESI+ found [M+H]=424.2

Example 532 WX Method 070

1-[(4-chlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(4-chlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(4-chlorobenzyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (3.0 g, 11.92 mmol) in N,N-dimethylformamide (25 mL) was added potassium carbonate (4.9 g, 35.76 mmol) and 1-(bromomethyl)-4-chlorobenzene (2.9 g, 14.3 mmol). The mixture was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-(4-chlorobenzyl)-1H-1,2,4-triazole-3-carboxylate (1.6 g, 54%) as white solids.

Step 2: 1-(4-chlorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(4-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylate (1.6 g, 6.41 mmol) and potassium hydroxide (719 mg, 12.82 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25° C. for 12 h. The ethanol was evaporated and the residue was diluted with water (20 mL). The mixture was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried to, obtain 1-(4-chlorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid (1.49 g, 98%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.64 (s, 1H), 7.40-7.34 (m, 4H), 5.47 (s, 2H).

Step 3: 1-[(4-chlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(4-chlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a solution of 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (42 mg, 0.22 mmol) 1-[(4-chlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (45 mg, 0.20 mmol) 1-hydroxybenzotriazole (27 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonium hydroxide in water) to afford 1-[(4-chlorophenyl)methyl]-N-[4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (50 mg, 53%) as white solid. The obtained racemic compound was separated by chiral SFC to give:

1-[(4-chlorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time=5.006 min) (18 mg, 36%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.70-8.68 (m, 1H), 7.41-7.39 (m, 2H), 7.20-7.22 (m, 2H), 6.94 (s, 1H), 5.49 (s, 2H), 4.95-4.44 (m, 1H), 4.38-4.30 (m, 2H), 3.26 (s, 3H), 2.66-2.63 (m, 1H), 2.32-2.29 (m, 1H). LCMS R_(T)=1.889 min, m/z=468.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.889 min, ESI+ found [M+H]=468.1.

1-[(4-chlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time=6.159 min) (16 mg, 32%) as white solids. ¹H NMR (400 MHz, DMSO-d6) δ8.82 (s, 1H), 8.70-8.68 (m, 1H), 7.41-7.39 (m, 2H), 7.20-7.22 (m, 2H), 6.94 (s, 1H), 5.49 (s, 2H), 4.95-4.44 (m, 1H), 4.38-4.30 (m, 2H), 3.26 (s, 3H), 2.66-2.63 (m, 1H), 2.32-2.29 (m, 1H). LCMS R_(T)=1.889 min, m/z=468.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.889 min, ESI+ found [M+H]=468.1.

SFC condition: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 533 WX Method 079

1-[(3-chlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(3-chlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 077 (RIP1K_experimental_3^(rd)_WX.doc). The obtained racemic compound was separated by SFC to give:

1-[(3-chlorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time=4.658 min) (14 mg, 27%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.69-8.67 (m, 1H), 7.46-7.32 (m, 3H), 7.28-7.25 (m, 1H), 6.94 (s, 1H), 5.50 (s, 2H), 4.49-4.44 (m, 1H), 4.37-4.32 (m, 2H), 3.26 (s, 3H), 2.65 (s, 1H), 2.46-2.42 (m, 1H). LC-MS R_(T)=1.883 min, m/z=468.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.883 min, ESI+ found [M+H]=468.1.

1-[(3-chlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time=5.731 min) (8 mg, 15%) as white solids. ¹H NMR (400 MHz, METHANOL-d4) 68.62 (s, 1H), 7.45-7.32 (m, 3H), 7.29-7.28 (m, 1H), 6.68 (s, 1H), 5.48 (s, 2H), 4.58-4.47 (m, 2H), 4.41-4.33 (m, 1H), 3.37 (s, 3H), 2.91-2.86 (m, 1H), 2.36-2.31 (m, 1H). LC-MS R_(T)=1.883 min, m/z=468.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.883 min, ESI+ found [M+H]=468.1.

SFC condition: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 534 WX Method 069

1-[(2,3-dichlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(2,3-dichlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(2, 3-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (1.5 g, 11.8 mmol) in N,N-dimethylformamide (25 mL) was added potassium carbonate (3.3 g, 23.6 mmol) and 1-(bromomethyl)-2,3-dichloro-benzene (3.4 g, 14.16 mmol). The mixture was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-(2,3-dichlorobenzyl)-1H-1,2,4-tri azole-3-carboxylate (1.91 g, 57%) as white solids, used as is in the next step.

Step 2: 1-(2, 3-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of solution of methyl 1-[(2,3-dichlorophenyl)methyl]-1,2,4-triazole-3-carboxylate (1.9 g, 6.68 mmol) and potassium hydroxide (749 mg, 13.36 mmol) in ethanol (40 mL) and water (5 mL) was stirred at 25° C. for 12 h. The ethanol was evaporated and the residue was diluted with water (20 mL). The mixture was adjusted to pH=4 by addition of 2 N HCl. The resulting solid was collected by filtration and dried to obtain 1-[(2, 3-dichlorophenyl) methyl]-1,2,4-triazole-3-carboxylic acid (1.7 g, 95%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.69 (s, 1H), 7.59-7.57 (m, 1H), 7.37-7.24 (m, 2H), 5.66 (s, 2H).

Step 3: 1-[(2,3-dichlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-[(2,3-dichlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a solution of 6-amino-4-methyl-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (42 mg, 0.22 mmol) 1-hydroxybenzotriazole (27 mg, 0.20 mmol) 1-[(2,3-dichlorophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (54 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonium hydroxide in water) to afford 1-[(2,3-dichlorophenyl)methyl]-N-[4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (50 mg, 49%) as white solid. The obtained racemic material was separated by chiral SFC to give:

1-[(2,3-dichlorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time=5.069 min) (14 mg, 27%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.68-8.66 (m, 1H), 7.67-7.64 (m, 1H), 7.41-7.37 (m, 1H), 7.21-7.19 (m, 1H), 6.94 (s, 1H), 5.65 (s, 2H), 4.47-4.38 (m, 1H), 4.38-4.29 (m, 2H), 3.27 (s, 3H), 2.67-2.65 (m, 1H), 2.33-2.31 (m, 1H). LCMS R_(T)=1.954 min, m/z=502.0 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.954 min, ESI+ found [M+H]=502.0.

1-[(2,3-dichlorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time=5.870 min) (16 mg, 31%) as white solids. ¹H NMR (400 MHz, DMSO-d6) δ8.84 (s, 1H), 8.68-8.66 (m, 1H), 7.67-7.64 (m, 1H), 7.41-7.37 (m, 1H), 7.21-7.19 (m, 1H), 6.94 (s, 1H), 5.65 (s, 2H), 4.47-4.38 (m, 1H), 4.38-4.29 (m, 2H), 3.27 (s, 3H), 2.67-2.65 (m, 1H), 2.33-2.31 (m, 1H). LCMS R_(T)=1.954 min, m/z=502.0 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.954 min, ESI+ found [M+H]=502.0.

SFC condition: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 535 WX Method 091

1-benzyl-N-(2,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: 3-chloro-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

To a solution of 9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (1.2 g, 7.26 mmol) in N,N-dimethylformamide (20 mL) was added 1-chloropyrrolidine-2,5-dione (776 mg, 5.81 mmol). The reaction mixture was stirred at 25° C. for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 3-chloro-9-methyl-6,7-dihydro-5H-imidazo [1,2-a][1,3]diazepin-8-one (700 mg, 48%) as a light yellow oil, used as is in the next step.

Step 2: 2-bromo-3-chloro-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

To a solution of 3-chloro-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (700 mg, 3.51 mmol) in N,N-dimethylformamide (10 mL) was added 1-bromo-2,5-pyrrolidinedione (499 mg, 2.81 mmol). The reaction mixture was stirred at 25° C. for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 2-bromo-3-chloro-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (670 mg, 68%) as a yellow solid, used as is in the next step. LCMS RT=1.791 min; m/z=278.0 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.791 ESI+ found [M+H]=278.0

Step 3: 3-chloro-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

A mixture of 2-bromo-3-chloro-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (670 mg, 2.41 mmol), cesium carbonate (784 mg, 2.41 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (302 mg, 2.41 mmol) and [1,1′-Bis(diphenylphosphino) ferrocene]dichloro palladium (II) (176 mg, 0.24 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated at 110° C. for 0.5 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford 3-chloro-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (120 mg, 23%) as a yellow oil, used as is in the next step.

Step 4: 3-chloro-7-iodo-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

To a solution of 3-chloro-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (250 mg, 1.17 mmol) in dichloromethane (30 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (816 mg, 7.02 mmol) and iodotrimethylsilane (1405 mg, 7.02 mmol) at −15° C. The reaction mixture was stirred at −15° C. for 2 h and iodine (891 mg, 3.51 mmol) was added. The mixture was stirred at −15° C. for another 2 h and quenched by addition of saturated aqueous sodium sulfite (10 mL). The solution was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 3-chloro-7-iodo-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (280 mg, 71%) as a colorless oil, used as is in the next step. LCMS RT=1.848 min; m/z=255.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.848 ESI+ found [M+H]=255.1

Step 5: 7-azido-3-chloro-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

A mixture of 3-chloro-7-iodo-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (280 mg, 0.82 mmol) and sodium azide (380 mg, 5.85 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The reaction mixture was added to ice water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.6) to afford 7-azido-3-chloro-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (200 mg, 95%) as a yellow oil, used as is in the next step, used as is in the next step.

Step 6: 7-amino-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

A mixture of 7-azido-3-chloro-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (200 mg, 0.79 mmol) and Pd/C (10%, 836 mg, 0.79 mmol) in 1,4-dioxane (5 mL) was hydrogenated (15 psi) for 5 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 7-amino-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (80 mg, 52%) as a yellow oil, used as is in the next step. LCMS RT=1.074 min; m/z=195.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.074 ESI+ found [M+H]=195.2

Step 7: 1-benzyl-N-(2,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of 1-benzyl-1,2,4-triazole-3-carboxylic acid (83 mg, 0.41 mmol) in N,N-dimethylformamide (5 mL) was added 7-amino-2,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (80 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (79 mg, 0.41 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (13% to 43% acetonitrile/0.05% ammonia hydroxide in water) to afford 1-benzyl-N-(2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1,2,4-triazole-3-carboxamide (42 mg, 27%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ8.56 (s, 1H), 7.39-7.32 (m, 5H), 6.78 (s, 1H), 5.47 (s, 2H), 4.55-4.50 (m, 1H), 4.21-4.15 (m, 1H), 4.03-3.98 (m, 1H), 3.36 (s, 3H), 2.85-2.79 (m, 1H), 2.29-2.23 (m, 1H), 2.19 (s, 3H). LCMS R_(T)=1.779 min, m/z=380.2 (M+H)⁺. LCMS RT=1.779 min; m/z=380.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.779 min, ESI+ found [M+H]=380.2

Example 536 WX Method 149

phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine

A mixture of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 1.29 mmol), pyridine (205 mg, 2.59 mmol), copper(II)acetate (470 mg, 2.59 mmol) and phenylboronic acid (237 mg, 1.94 mmol) in dichloromethane (5 mL) was heated at 80° C. for 15 min under microwave conditions. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (250 mg, 84%) as a pale yellow solid, used as is in the next step.

Step 2: 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

To a solution of 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.87 mmol) in dimethyl sulfoxide (10 mL) were added 1,4-diazabicyclo[2.2.2]octane (10 mg, 0.09 mmol) and sodium cyanide (85 mg, 1.73 mmol) in water (1 mL). The mixture was stirred at 25° C. for 3 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (40% ethyl acetate in petroleum ether) to afford 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (80 mg, 42%) as a yellow solid. LCMS R_(T)=1.037 min; m/z=222.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.037 min, ESI+ found [M+H]=222.1.

Step 3: methyl 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

A solution of 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (80 mg, 0.36 mmol) in methanol (5 mL) was added HCl (4N in methanol, 1.5 mL). The mixture was stirred at 20° C. for 20 h and 50° C. for 3 h. The reaction solution was concentrated under reduced pressure to give crude methyl 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (90 mg, 98%) as a yellow solid. LCMS R_(T)=1.145 min; m/z=255.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.145 min, ESI+ found [M+H]=255.1.

Step 4: 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

A mixture of methyl 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (90 mg, 0.37 mmol) and lithium hydroxide hydrate (77 mg, 1.83 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25° C. for 2 h. The organic solvent was evaporated under reduced pressure and the aqueous phase was adjusted to pH=4 by addition of 2N HCl. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give crude 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (50 mg, 57%) as a yellow solid.

LCMS R_(T)=1.015 min; m/z=241.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.015 min, ESI+ found [M+H]=241.1.

Step 5: phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (22 mg, 0.11 mmol), 1-phenylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (25 mg, 0.10 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.12 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35% to 65%/0.05% ammonia hydroxide in water) to give phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (30.9 mg, 71%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ9.61 (s, 1H), 9.17 (d, J=8.0 Hz, 1H), 8.79 (s, 1H), 8.23 (d, J=8.0 Hz, 2H), 7.65-7.61 (m, 2H), 7.52 (d, J=7.2 Hz, 1H), 7.45-7.40 (m, 1H), 7.35-7.28 (m, 3H), 4.95-4.90 (m, 1H), 4.62-4.54 (m, 2H). LCMS R_(T)=0.846 min; m/z=415.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.846 min, ESI+ found [M+H]=415.1.

Example 537 WX Method 174

4-(1-hydroxycyclobutyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5benzoxazepin-3-yl]pyrimidine-2

Step 1: 1-(2-bromopyrimidin-4-yl)cyclobutanol

To a solution of cyclobutanone (1.48 g, 21.06 mmol) and 2-bromo-4-iodo-pyrimidine (2.0 g, 7.02 mmol) in tetrahydrofuran (60 mL) was added isopropylmagnesiumbromide (1.0 M in tetrahedron, 10.5 mL, 10.5 mmol) at −70° C. The mixture was stirred at −70° C. for 1 h and quenched by addition of saturated ammonium chloride (30 mL). The resulting solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×10 ml), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give 1-(2-bromopyrimidin-4-yl)cyclobutanol (350 mg, 22%) as a yellow oil. LC-MS R_(T)=0.52 min, m/z=228.8 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.52/min, ESI+ found [M+H]=228.8

Step 3: 4-(1-hydroxycyclobutyl)pyrimidine-2-carbonitrile

To a solution of 1-(2-bromopyrimidin-4-yl)cyclobutanol (350 mg, 1.53 mmol) in dimethyl sulfoxide (5 mL) was added 1,4-diazabicyclo[2.2.2]octane (86 mg, 0.76 mmol) and sodium cyanide (149 mg, 3.06 mmol) in water (2.5 mL). The mixture was stirred at 25° C. for 16 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 4-(1-hydroxycyclobutyl)pyrimidine-2-carbonitrile (260 mg, 97%) as a white solid. LC-MS R_(T)=0.60 min, m/z=175.8 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.60/min, ESI+ found [M+H]=175.8

Step 4: methyl 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylate

A solution of 4-(1-hydroxycyclobutyl)pyrimidine-2-carbonitrile (100 mg, 0.57 mmol) in methanol (3 mL) was HCl (4N in methanol, 14.4 mL). The reaction mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.3) to afford methyl 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylate (16 mg, 14%) as yellow oil. LC-MS R_(T)=1.77 min, m/z=209.0 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% trifluoacetic acid over 4 mins) retention time 1.77/min, ESI+ found [M+H]=209.0.

Step 5: 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylic acid

A mixture of methyl 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylate (16 mg, 0.08 mmol) and lithium hydroxide (9 mg, 0.38 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25° C. for 16 h. The mixture was adjusted to pH=6 by addition of 1N HCl and concentrated under reduced pressure to give crude 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylic acid (13 mg, 87%) as a yellow solid.

Step 6: 4-(1-hydroxycyclobutyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (22 mg, 0.11 mmol), 4-(1-hydroxycyclobutyl)pyrimidine-2-carboxylic acid (22 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (26 mg, 0.14 mmol) and 1-hydroxybenzotriazole (18 mg, 0.14 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonia hydroxide in water) to give 4-(1-hydroxycyclobutyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide (11.3 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.89 (d, J=5.2 Hz, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.46-7.44 (m, 1H), 7.34-7.27 (m, 2H), 7.26-7.25 (m, 1H), 5.06-5.04 (m, 1H), 4.73-4.72 (m, 1H), 4.44-4.42 (m, 1H), 3.45 (s, 3H), 2.72-2.68 (m, 2H), 2.43-2.35 (m, 2H), 2.12-2.07 (m, 2H). LCMS RT=1.938 min; m/z=369.1 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.938 min, ESI+ found [M+H]=369.1.

Example 538

1-[(3-chlorophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 077. The crude was purified by RP-HPLC (ACN 35-65%/0.05% ammonia hydroxide in water) to afford 1-[(3-chlorophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (41.56 mg, 41%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 7.37-7.25 (m, 4H), 6.18 (s, 1H), 5.47 (s, 2H), 4.61-4.58 (m, 1H), 4.40-4.26 (m, 2H), 3.28 (s, 3H), 2.87-2.81 (m, 1H), 2.32-2.30 (m, 1H), 1.97-1.93 (m, 1H), 1.05-1.03 (m, 2H), 0.84-0.81 (m, 2H). LC-MS R_(T)=0.802 min, m/z=440.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.802 min, ESI+ found [M+H]=440.1

Example 539 WX Method 142

1-isopropyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: 6-chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine

A mixture of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 3.25 mmol), 2-iodopropane (553 mg, 3.25 mmol) and potassium carbonate (897 mg, 6.50 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 6-chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 47%) as yellow solid, used as is in the next step.

Step 2: 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

To a solution of 6-chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.53 mmol) in dimethyl sulfoxide (5 mL) and water (5 mL) was added 1,4-diazabicyclo[2.2.2]octane (34 mg, 0.21 mmol) and sodium cyanide (150 mg, 3.05 mmol). The reaction mixture was stirred at 25° C. for 3 h and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (140 mg, 49%) as yellow oil, used as is in the next step.

Step 3: methyl 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

To a solution of 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (140 mg, 0.75 mmol) in methanol (5 mL) was added HCl (4N in methanol, 4 mL). The reaction mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure to afford crude methyl 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (120 mg, 73%) as yellow oil, used as is in the next step.

Step 4: 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

A mixture of methyl 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (120 mg, 0.54 mmol) and lithium hydroxide hydrate (229 mg, 5.45 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25° C. for 2 h. The mixture was adjusted to pH=5 by addition of 1N HCl and extracted with ethyl acetate (3×15 mL). The combined organic layers were concentrated under reduced pressure to afford 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 27%) as a colorless oil, used as is in the next step.

Step 5: 1-isopropyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

A mixture of (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (34 mg, 0.17 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (24 mg, 0.17 mmol), 1-isopropylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 0.15 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (33 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30% to 60%, 0.05% ammonium hydroxide in water) to afford 1-isopropyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (32.8 mg, 58%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 9.35 (s, 1H) 8.38 (s, 1H), 6.14 (s, 1H), 5.47-5.42 (m, 1H), 4.65-4.60 (m, 1H), 4.37-4.26 (m, 2H), 3.37 (s, 3H), 3.00-2.94 (m, 1H), 2.35-2.27 (m, 4H), 1.59 (d, J=6.8 Hz, 6H). LCMS R_(T)=0.733 min, m/z=383.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.733 min, ESI+ found [M+H]=383.1.

Example 540

1-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 149. The crude was purified by RP-HPLC (acetonitrile 30% to 60%/0.05% ammonia hydroxide in water) to give 1-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (20 mg, 46%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.20 (d, J=8.0 Hz, 1H), 8.77 (s, 1H), 8.23 (d, J=7.6 Hz, 2H), 7.64-7.59 (m, 2H), 7.46-7.41 (m, 1H), 6.15 (s, 1H), 4.43-4.39 (m, 1H), 4.32-4.27 (m, 1H), 4.18-4.15 (m, 1H), 3.26 (s, 3H), 2.74-2.69 (m, 1H), 2.37-2.34 (m, 1H), 2.18 (s, 3H). LCMS R_(T)=0.792 min; m/z=417.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.792 min, ESI+ found [M+H]=417.1.

Example 541 WX Method 071

2-benzyl-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yltetrazole-5-carboxamide

Step 1: methyl 2-benzyl-2H-tetrazole-5-carboxylate

To a solution of ethyl 2H-tetrazole-5-carboxylate (1.0 g, 7.04 mmol) in N,N-dimethylformamide (20 mL) was added benzyl bromide (1.2 g, 7.04 mmol) and potassium carbonate (972 mg, 7.04 mmol). The mixture was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 2-benzyl-2H-tetrazole-5-carboxylate (200 mg, 13%) as a white solid, used as is in the next step.

Step 2: 2-benzyl-2H-tetrazole-5-carboxylic acid

A mixture of methyl 2-benzyltetrazole-5-carboxylate (200 mg, 0.92 mmol) and triethylamine (185 mg, 1.83 mmol) in ethanol (20 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The solution was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried under reduced pressure to obtain 2-benzyl-2H-tetrazole-5-carboxylic acid (130 mg, 69.5%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ7.44-7.36 (m, 5H), 5.94 (s, 2H).

Step 3: 2-benzyl-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yltetrazole-5-carboxamide

A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (37 mg, 0.19 mmol), 2-benzyltetrazole-5-carboxylic acid (31 mg, 0.15 mmol), (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (25 mg, 0.13 mmol) and 1-hydroxybenzotriazole (26 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20-50%/0.05% ammonium hydroxide in water) to give 2-benzyl-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yltetrazole-5-carboxamide (11 mg, 12%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.37 (m, 5H), 6.12 (s, 1H) 5.94 (s, 2H), 4.58-4.53 (m, 1H), 4.35-4.29 (m, 1H), 4.26-4.22 (m, 1H), 3.32 (s, 3H), 2.84-2.78 (m, 1H), 2.34-2.25 (m, 4H). LCMS R_(T)=0.938 min, m/z=381.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.938 min, ESI+ found [M+H]=381.2

Example 542

2-benzyl-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yltetrazole-5-carboxamide

Amide coupling prepared in a similar fashion to WX Method 071. The crude was purified by RP-HPLC (acetonitrile 28-58%/0.05% ammonium hydroxide in water) to give 2-benzyl-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yltetrazole-5-carboxamide (10 mg, 11%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.44-7.34 (m, 5H), 6.00 (s, 1H), 5.93 (s, 2H), 4.57-4.52 (m, 1H), 4.34-4.26 (m, 1H), 4.24-4.14 (m, 1H), 3.30 (s, 3H), 2.86-2.81 (m, 1H), 2.34-2.30 (m, 1H), 1.94-1.85 (m, 1H), 0.96-0.90 (m, 2H), 0.77-0.68 (m, 2H). LCMS R_(T)=1.002 min, m/z=407.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.002 min, ESI+ found [M+H]=407.2

Example 543

1-cyclopentyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 147. The crude was purified by RP-HPLC (acetonitrile 26% to 56%/0.05% ammonia hydroxide in water) to give 1-cyclopentyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (30.2 mg, 56%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 9.15 (d, J=8.0 Hz, 1H), 8.51 (s, 1H), 6.16 (s, 1H), 5.49-5.41 (m, 1H), 4.47-4.10 (m, 3H), 3.25 (s, 3H), 2.77-2.66 (m, 1H), 2.38-2.29 (m, 1H), 2.23-2.11 (m, 5H), 2.06-1.86 (m, 4H), 1.80-1.65 (m, 2H). LCMS R_(T)=0.787 min; m/z=409.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.787 min, ESI+ found [M+H]=409.1

Example 544 WX Method 161

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide

Step 1: 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-5-one

To a solution of 2,2,6,6-tetramethylpiperidine (13.4 g, 94.6 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M in hexanes, 50.0 mL, 125.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 2-chloropyrimidine-5-carboxylic acid (5.0 g, 31.5 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and dihydro-2H-pyran-3(4H)-one (6.3 g, 63.1 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, 30% ethyl acetate in petroleum ether) to give 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-5-one (900 mg, 12%) as light yellow solid, use as is in the next step.

Step 2: 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-5-ol

To a solution of 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-5-one (700 mg, 2.90 mmol) in toluene (30 mL) was added diisobutylaluminum hydride (7.3 mL, 7.27 mmol, 1.0 M in toluene) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h and quenched by addition of saturated potassium tartrate tetrahydrate (10 mL). The resulting mixture was stirred at 25° C. for 1 h and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, eluting 50% ethyl acetate in petroleum ether) to afford 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-5-ol (260 mg, 37%) as white solid, used as is in the next step.

Step 3: 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]

To a solution of 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-5-ol (260 mg, 1.1 mmol) and 2,2,2-trifluoroacetic acid (1.6 mL, 21.9 mmol) in dichloromethane (25 mL) was added triethylsilane (1.6 mL, 10.20 mmol). The mixture was stirred at 25° C. for 15 h and concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran](240 mg, 99%) as colorless oil, used as is in the next step.

Step 4: 2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carbonitrile

To a solution of 2-chloro-2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran](410 mg, 1.80 mmol) in dimethyl sulfoxide (20 mL) was added 1,4-diazabicyclo[2.2.2]octane (41 mg, 0.40 mmol) and sodium cyanide (280 mg, 5.70 mmol) in water (4 mL). The mixture was stirred for 7 h at 25° C. and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, eluting 20-40% ethyl acetate in petroleum ether) to afford 2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carbonitrile (210 mg, 53%) as colorless oil, used as is in the next step.

Step 5: methyl 2′,4′5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carboxylate

To a solution of 2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carbonitrile (210 mg, 1.00 mmol) in methanol (12 mL) was added HCl (4N in methanol, 2.5 mL) at 0° C. The mixture was stirred at 25° C. for 15 h and concentrated under reduced pressure to afford crude methyl 2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carboxylate (210 mg, 87%) as a white solid, used as is in the next step.

Step 6: 2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carboxylic acid

A mixture of methyl 2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carboxylate (210 mg, 0.8 mmol) and lithium hydroxide (201 mg, 8.4 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred for 2 h at 25° C. The organic solvent was reduced pressure and the aqueous phase was adjusted to pH=4 by addition of 1N HCl. The mixture was concentrated under reduced pressure to give crude to 2′,4′,5′,6′-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,3′-pyran]-2-carboxylic acid (180 mg, 91%) as a light yellow solid, used as is in the next step.

Step 7: N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 160 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonia hydroxide in water) to give N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo [3,4-d]pyrimidine-7,3′-tetrahydropyran]-2-carboxamide (7.7 mg, 12%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ8.52 (s, 1H), 6.14 (s, 1H), 5.22 (s, 2H), 4.62-4.56 (m, 1H), 4.34-4.24 (m, 2H), 3.95-3.90 (m, 1H), 3.79-3.65 (m, 3H), 3.35 (s, 3H), 2.96-2.90 (m, 1H), 2.31-2.20 (m, 5H), 2.07-2.03 (m, 1H), 1.94-1.90 (m, 1H), 1.77-1.73 (m, 1H). LCMS R_(T)=0.580 min; m/z=413.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.580 min, ESI+ found [M+H]=413.1.

Example 545

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[3H-furo[3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 158 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by RP-HPLC (acetonitrile 20% to 50%/0.05% hydrochloric acid in water) to give N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[3H-furo [3,4-c]pyridine-1,3′-tetrahydropyran]-6-carboxamide (15.5 mg, 18%). ¹H NMR (400 MHz, CD₃OD) δ8.59 (s, 1H), 8.03 (s, 1H), 6.12 (s, 1H), 5.24-5.15 (m, 2H), 4.59-4.54 (m, 1H), 4.36-4.19 (m, 2H), 3.87-3.61 (m, 4H), 3.34 (s, 3H), 2.97-2.84 (m, 1H), 2.28-2.19 (m, 4H), 2.07-1.89 (m, 3H), 1.78-1.70 (m, 1H). LCMS R_(T)=0.887 min; m/z=412.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.887 min, ESI+ found [M+H]=412.2.

Example 546 WX Method 095

1-benzyl-N-(3,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1,2,4-triazole-3-carboxamide

Step 1: 3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

A mixture of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (500 mg, 4.01 mmol), 3-chloro-9-methyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (400 mg, 2 mmol), bis(1-adamantyl)-butyl-phosphane (36 mg, 0.10 mmol) and potassium carbonate (831 mg, 6.01 mmol) in toluene (3 mL) and water (1 mL) was heated at 110° C. for 2 h under microwave conditions. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford 3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (80 mg, 22%) as a yellow oil, used as is in the next step.

Step 2: 7-iodo-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

To a solution of 3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (40 mg, 0.22 mmol) in dichloromethane (10 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (155 mg, 1.37 mmol) and iodotrimethylsilane (268 mg, 1.34 mmol) at −15° C. The reaction mixture was stirred at −15° C. for 2 h and iodine (170 mg, 0.67 mmol) was added. The mixture was stirred at −15° C. for another 2 h and quenched by addition of saturated aqueous sodium sulfite (10 mL). The resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 7-iodo-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (40 mg, 58%) as a colorless oil, used as is in the next step. LCMS R_(T)=1.491 min; m/z=306.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.491 ESI+ found [M+H]=306.1

Step 3: 7-azido-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

A mixture of 7-iodo-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (40 mg, 0.13 mmol) and sodium azide (70 mg, 1.08 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.6) to afford 7-azido-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (20 mg, 69%) as a yellow oil, used as is in the next step.

Step 4: 7-amino-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one

A mixture of 7-azido-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (20 mg, 0.09 mmol) and Pd/C (10%, 96 mg, 0.09 mmol) in 1,4-dioxane (5 mL) was hydrogenated (15 psi) for 5 h and filtered. The filtrate was concentrated under reduced pressure to afford 7-amino-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8(9H)-one (10 mg, 56%) as a yellow oil, used as is in the next step.

Step 5: 1-benzyl-N-(2,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (10 mg, 0.05 mmol), 7-amino-3,9-dimethyl-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-8-one (10 mg, 0.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (10 mg, 0.05 mmol) and 1-hydroxybenzotriazole (7 mg, 0.05 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (13% to 43% acetonitrile/0.05% ammonia hydroxide in water) to afford

1-benzyl-N-(3,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1,2,4-triazole-3-carboxamide (3.9 mg, 19%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.39-7.35 (m, 5H), 6.71 (s, 1H), 5.47 (s, 2H), 4.51-4.46 (m, 1H), 4.22-4.16 (m, 1H), 3.95-3.87 (m, 1H), 3.37 (s, 3H), 2.84-2.74 (m, 1H), 2.29-2.19 (m, 4H). LCMS R_(T)=1.792 min, m/z=380.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.792 min, ESI+ found [M+H]=380.1.

Examples 547 and 548 WX Method 084

1-benzyl-N-(6S)-4-methyl-5-oxo-2-[(1 S)-2,2-difluorocyclopropylmethyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-benzyl-N-(6S)-4-methyl-5-oxo-2-[(1R)-2,2-difluorocyclopropylmethyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: 2-allyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride (4.2 g, 5.74 mmol), cesium fluoride (26.14 g, 172.1 mmol), allylboronicacidpinacolester (14.46 g, 86.07 mmol), 2-bromo-4-methyl-7,8-dihydro-6h-pyrazolo[1,5-a][1,3]diazepin-5-one (14.0 g, 53.4 mmol) in tetrahydrofuran (500 mL) was stirred at 70° C. under nitrogen atmosphere for 16 h and then concentrated under reduced pressure. The residue was diluted with dichloromethane (200 mL), washed water (2×100 mL), brine (100 mL), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 1% methanol in dichloromethane) to give 2-allyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (6.55 g, 60%). LCMS R_(T)=0.63 min, m/z=205.8 [M+H]⁺

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.63 min, ESI+ found [M+H]=205.8.

Step 2: 2-((2,2-difluorocyclopropyl)methyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 2-allyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (5.0 g, 24.4 mmol), tetrabutylammonium bromide (235 mg, 0.7 mmol) and [bromo(difluoro)methyl]-trimethyl-silane (24.7 g, 121.8 mmol) in toluene (50 mL) was heated at 110° C. for 5 h in a sealed tube. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 3% methyl in dichloromethane) to give 2-[(2,2-difluorocyclopropyl)methyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (3.3 g, 53%) as a brown oil. LCMS RT=0.63 min, m/z=255.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.63 min, ESI+ found [M+H]=255.9.

Step 3: 2-((2,2-difluorocyclopropyl)methyl)-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 2-((2,2-difluorocyclopropyl)methyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.4 g, 13.32 mmol) in dichloromethane (100 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (20.82 g, 159.84 mmol) and iodotrimethylsilane (32.0 g, 159.84 mmol) at −15° C. The mixture was stirred at −15° C. for 1.5 h and iodine (20.28 g, 79.92 mmol) was added in one portion. The mixture was stirred for another 3 h and then quenched by addition of 5% aqueous sodium thiosulfate (200 mL). The solution was extracted with dichloromethane (2×200 mL). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 2-((2,2-difluorocyclopropyl)methyl)-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]di azepin-5(6H)-one (2.2 g, 43%) as a yellow oil. LCMS RT=0.67 min, m/z=381.9 [M+H]+.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.67 min, ESI+ found [M+H]=381.9.

Step 4: 6-azido-2-((2,2-difluorocyclopropyl)methyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][11, 3]diazepin-5(6H)-one

A mixture of 2-((2,2-difluorocyclopropyl)methyl)-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (2.2 g, 5.77 mmol) and sodium azide (0.56 g, 8.66 mmol) in N,N-dimethylformamide (50 mL) was stirred at 25° C. for 16 h and diluted with ethyl acetate (50 mL). The solution was washed with water (2×50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 6-azido-2-((2,2-difluorocyclopropyl)methyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]di azepin-5(6H)-one (1.5 g, 88%) as a white solid. LCMS RT=0.66 min, m/z=296.9 [M+H]+.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.66 min, ESI+ found M+H]=296.9.

Step 5: 6-amino-2-((2,2-difluorocyclopropyl)methyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A solution of 6-azido-2-[(2,2-difluorocyclopropyl)methyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.5 g, 5.06 mmol) in tetrahydrofuran (50 mL) was added water (10 mL) and 80% polymer-bound triphenylphosphine (6.0 g, 18.3 mmol). The mixture was stirred at 25° C. for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to give 6-amino-2-[(2,2-difluorocyclopropyl)methyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.0 g, 73%) as a yellow oil. LCMS RT=0.54 min, m/z=270.8 [M+H]+.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.54 min, ESI+ found [M+H]=270.8.

Step 6: 1-benzyl-N-(6S)-4-methyl-5-oxo-2-[(1 S)-2,2-difluorocyclopropylmethyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-benzyl-N-(6S)-4-methyl-5-oxo-2-[(1R)-2,2-difluorocyclopropylmethyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2-[(2,2-difluorocyclopropyl)methyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (150 mg, 0.56 mmol), 1-hydroxybenzotriazole (112 mg, 0.83 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (112 mg, 0.56 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (106 mg, 0.56 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (33% to 63% acetonitrile, 0.05% ammonia hydroxide in water) to give 1-benzyl-N-[2-[(2,2-difluorocyclopropyl)methyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (110 mg, 44%) as a white solid. The racemate was separated by chiral SFC to give:

1-benzyl-N-(6S)-4-methyl-5-oxo-2-[(1 S)-2,2-difluorocyclopropylmethyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.169 min) (9.1 mg, 8.3%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.58 (s, 1H), 7.48-7.20 (m, 5H), 6.23 (s, 1H), 5.43 (s, 2H), 4.57-4.53 (m, 1H), 4.38-4.34 (m, 1H), 4.26-4.22 (m, 1H), 3.35 (s, 3H), 2.95-2.65 (m, 3H), 2.40-2.20 (m, 1H), 2.05-1.80 (m, 1H), 1.65-1.45 (m, 1H), 1.25-1.10 (m, 1H). LCMS RT=0.684 min, m/z=456.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.684 min, ESI+ found [M+H]=456.0.

1-benzyl-N-(6S)-4-methyl-5-oxo-2-[(1R)-2,2-difluorocyclopropylmethyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.225 min) (8.9 mg, 8.1%) as a white solid. ¹H NMR (400 MHz, CD3OD) 8.59 (s, 1H), 7.48-7.20 (m, 5H), 6.24 (s, 1H), 5.49 (s, 2H), 4.57-4.53 (m, 1H), 4.37-4.35 (m, 1H), 4.28-4.23 (m, 1H), 3.35 (s, 3H), 2.95-2.65 (m, 3H), 2.40-2.20 (m, 1H), 2.05-1.80 (m, 1H), 1.65-1.45 (m, 1H), 1.25-1.10 (m, 1H).

LCMS RT=0.694 min, m/z=456.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.694 min, ESI+ found [M+H]=456.1.

SFC conditions: Method: Column: Chiralpak AY-3, 150×4.6 mm I.D., 3 um Mobile phase: 50% ethanol (0.05% DEA) in CO2 Flow rate: 2.0 mL/min Wavelength: 220 nm.

Example 549 WX Method 173

4-(1-hydroxy-1-methyl-propyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide

Step 1: 2-bromo-4-iodopyrimidine

To a solution of chloro-(2,2,6,6-tetramethyl-1-piperidyl)magnesium (1.5 M in tetrahedron, 39.0 mL, 58.1 mmol) in tetrahydrofuran (140 mL) was added 2-bromopyrimidine (8.4 g, 52.8 mmol) at −55° C. over 20 min. The resulting mixture was stirred for 1.5 h at −55° C. and zinc dichloride (1 M in tetrahedron, 58.0 mL, 58.0 mmol) was slowly added. After addition, the mixture was warmed up to 25° C. and a solution of iodine (20.1 g, 79.2 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred for 45 min and quenched by addition of saturated ammonium chloride (50 mL) and saturated sodium thiosulfate (150 mL). The mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% petroleum ether in ethyl acetate) to afford 2-bromo-4-iodopyrimidine (4.0 g, 27%) as a white solid.

Step 2: 2-(2-bromopyrimidin-4-yl)butan-2-ol

To a solution of methyl ethyl ketone (2.0 g, 28.08 mmol) and 2-bromo-4-iodo-pyrimidine (4.0 g, 14.04 mmol) in tetrahydrofuran (30 mL) was added isopropyl magnesium bromide (1.0 M in tetrahedron, 16.2 mL, 16.2 mmol) at −60° C. The mixture was stirred at −60° C. for 1 h and quenched by addition of saturated ammonium chloride (30 mL). The resulting solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×10 ml), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% petroleum ether in ethyl acetate) to give the product 2-(2-bromopyrimidin-4-yl)butan-2-ol (1.0 g, 31%) as a yellow oil. LC-MS R_(T)=2.45 min, m/z=231.0 (M+H)⁺.

LCMS (0-30% acetonitrile in water+0.03% trifluoacetic acid over 4.0 mins) retention time 2.45/min, ESI+ found [M+H]=231.0

Step 3: 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carbonitrile

To a solution of 2-(2-bromopyrimidin-4-yl)butan-2-ol (1.0 g, 4.00 mmol) in dimethyl sulfoxide (5 mL) was added 1,4-diazabicyclo[2.2.2]octane (243 mg, 2.16 mmol) and sodium cyanide (400 mg, 8.16 mmol) in water (2.5 ml). The mixture was stirred at 25° C. for 16 h and extracted with ethyl acetate (3×25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% petroleum ether in ethyl acetate) to afford 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carbonitrile (600 mg, 78%) as a white solid.

LC-MS R_(T)=1.48 min, m/z=178.0 (M+H)⁺.

LCMS (0-30% acetonitrile in water+0.03% trifluoacetic acid over 4 mins) retention time 1.48/min, ESI+ found [M+H]=178.0

Step 4: 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylate

A solution of 4-(1-hydroxycyclobutyl)pyrimidine-2-carbonitrile (600 mg, 3.39 mmol) in methanol (5 mL) was added HCl (1M in methanol, 6.77 mL). The reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated sodium bicarbonate (20 mL). The resulting solution was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.3) to afford 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylate (300 mg, 42%) as yellow oil.

LC-MS R_(T)=2.10 min, m/z=211.0 (M+H)⁺.

LCMS (0-30% acetonitrile in water+0.03% trifluoacetic acid over 4 mins) retention time 2.10/min, ESI+ found [M+H]=211.0.

Step 5: 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylic acid

A mixture of 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylate (50 mg, 0.24 mmol) and lithium hydroxide (29 mg, 1.19 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25° C. for 16 h. The mixture was adjusted to pH=6 by addition of 1N HCl and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 4-(1-hydroxy-1-methyl-propyl) pyrimidine-2-carboxylic acid (30 mg, 64%) as a white solid.

Step 6: 4-(1-hydroxy-1-methyl-propyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (29 mg, 0.15 mmol), 4-(1-hydroxy-1-methyl-propyl)pyrimidine-2-carboxylic acid (30 mg, 0.15 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (35 mg, 0.18 mmol) and 1-hydroxybenzotriazole (25 mg, 0.18 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (18% to 48% acetonitrile/0.05% ammonia hydroxide in water) to give 4-(1-hydroxy-1-methyl-propyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrimidine-2-carboxamide (27 mg, 47%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.89 (d, J=5.6 Hz, 1H), 7.84 (d, J=5.2 Hz, 1H), 7.49-7.41 (m, 1H), 7.34-7.24 (m, 3H), 5.06-5.02 (m, 1H), 4.70-4.66 (m, 1H), 4.47-4.42 (m, 1H), 3.44 (s, 3H), 2.01-1.87 (m, 2H), 1.56 (s, 3H), 0.81-0.77 (m, 3H). LCMS R_(T)=1.971 min; m/z=371.2 (M+H)⁺.

LCMS (0-60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.971 min, ESI+ found [M+H]=371.2.

Example 550

5-[(4-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-4H-1,2,4-triazole-3-carboxamide and 5-[(4-fluorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-4H-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 011. The crude was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonium hydroxide in water) to give 5-1-(4-fluorobenzyl)-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (50 mg, 53%) as white solid. The racemic material was separated by chiral SFC to give:

5-[(4-fluorophenyl)methyl]-N-(6R)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 2, Retention time=3.822 min) (14 mg, 27%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ7.33-7.29 (m, 2H), 7.07-7.03 (m, 2H), 6.67 (s, 1H), 4.56-4.47 (m, 2H), 4.42-4.33 (m, 1H), 4.14 (s, 2H), 3.37 (s, 3H), 2.94-2.85 (m, 1H), 2.35-2.28 (m, 1H). LC-MS R_(T)=1.126 min, m/z=452.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.126 min, ESI+ found [M+H]=452.1.

5-[(4-fluorophenyl)methyl]-N-(6 S)-4-methyl-5-oxo-2-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-4H-1,2,4-triazole-3-carboxamide (Peak 1, Retention time=3.495 min) (16 mg, 31%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ7.33-7.29 (m, 2H), 7.07-7.03 (m, 2H), 6.67 (s, 1H), 4.56-4.47 (m, 2H), 4.42-4.33 (m, 1H), 4.14 (s, 2H), 3.37 (s, 3H), 2.94-2.85 (m, 1H), 2.35-2.28 (m, 1H). LC-MS R_(T)=1.128 min, m/z=452.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.128 min, ESI+ found [M+H]=452.1.

SFC conditions: Column Chiralpak AS-H 250×4.6 mm I.D., 5 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5.0 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temperature: 35° C.

Example 551

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,3′-tetrahydrofuran]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 162 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by RP-HPLC (6% to 36% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo [3,4-d]pyrimidine-7,3′-tetrahydrofuran]-2-carboxamide (60 mg, 64%). ¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 1H), 6.13 (s, 1H), 5.19 (s, 2H), 4.62-4.57 (m, 1H), 4.37-4.21 (m, 2H), 4.18-4.00 (m, 4H), 3.35 (s, 3H), 2.99-2.88 (m, 1H), 2.50-2.41 (m, 1H), 2.35-2.27 (m, 5H).

LC-MS R_(T)=1.146 min, m/z=399.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.146 min, ESI+ found [M+H]=399.2.

Example 552

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 164 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by RP-HPLC (17% to 47% acetonitrile/0.05% ammonia hydroxide in water) to give N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo [3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide (42.9 mg, 47%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.79 (s, 1H), 6.13 (s, 1H), 5.11 (s, 2H), 4.59-4.57 (m, 1H), 4.33-4.25 (m, 2H), 3.35 (s, 3H), 2.98-2.91 (m, 1H), 2.31-2.25 (m, 4H), 2.13-1.99 (m, 4H), 1.94-1.91 (m, 4H). LC-MS R_(T)=1.850 min, m/z=397.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.850 min, ESI+ found [M+H]=397.2.

Example 553

8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 119 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by PR-HPLC (32% to 62% acetonitrile/0.05% ammonia hydroxide in water) to give 8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6,7,8-tetrahydro-[1, 2,4]triazolo[1,5-a]pyridine-2-carboxamide (4 mg, 33%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.45-7.39 (m, 1H), 7.36-7.20 (m, 6H), 7.16 (d, J=8.0 Hz, 2H), 5.02-4.95 (m, 1H), 4.58-4.51 (m, 1H), 4.40-4.32 (m, 4H), 3.39 (s, 3H), 2.40-2.33 (m, 1H), 2.24-2.03 (m, 3H). LCMS R_(T)=0.831 min, m/z=418.0 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 0.831 min, ESI+ found [M+H]=418.0

Example 554 WX Method 119

8-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: 8-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carbonitrile

To a mixture of 8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 2.38 mmol) and cuprous cyanide (234 mg, 2.62 mmol) in acetonitrile (30 mL) was added isopentyl nitrite (0.45 mL, 3.33 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then heated at 80° C. for 4 h. After cooled to 0° C., the mixture was added aqueous sodium hydroxide (2N, 8 mL), saturated sodium bicarbonate (120 mL) and dichloromethane (150 mL). The mixture was filtered and the organic phase was washed with brine (50 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% ethyl acetate in petroleum ether) to afford 8-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carbonitrile (50 mg, 10%) as a white solid. LCMS R_(T)=1.053 min, m/z=221.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.053 min, ESI+ found [M+H]=221.1

Step 2: methyl 8-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

A solution of 8-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carbonitrile carbonitrile (50 mg, 0.22 mmol) in HCl (2N in methanol, 4.0 mL, 8.0 mmol) was stirred at 20° C. for 20 h and concentrated under reduced pressure to give crude methyl 8-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (30 mg, 52%) as a white solid. LCMS R_(T)=0.778 & 0.844 min, m/z=253.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.778 min, ESI+ found [M+H]=253.9; retention time 0.844 min, ESI+ found [M+H]=253.9

Step 3: methyl 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

A mixture of methyl 8-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (30 mg, 0.12 mmol) and Pd/C (10%, 126 mg, 0.12 mmol) in methanol (10 mL) was hydrogenated (50 psi) for 1 h and filtered. The filtrate was concentrated under reduced pressure to give crude methyl 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (20 mg, 66%) as a white solid. LCMS R_(T)=0.729 min, m/z=257.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.729 min, ESI+ found [M+H]=257.9

Step 4: 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

A mixture of methyl 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (20 mg, 0.08 mmol) and lithium hydroxide hydrate (16 mg, 0.39 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25° C. for 4 h. The solution was diluted with water (20 mL) and adjusted to pH=4 by addition of 2N HCl. The resulting solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo [1,5-a]pyridine-2-carboxylic acid (10 mg, 53%), used as is in the next step.

Step 5: 8-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

A mixture of 8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (10 mg, 0.04 mmol), 1-hydroxybenzotriazole (7 mg, 0.05 mmol), (6s)-6-amino-2,4-dimethyl-7,8-dihydro-6h-pyrazolo[1,5-a][1,3]diazepin-5-one (9 mg, 0.05 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (9 mg, 0.05 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (36% acetonitrile/0.05% ammonia hydroxide in water) to give 8-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (4.5 mg, 26%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ7.39-7.23 (m, 3H), 7.20-7.08 (m, 2H), 6.10 (s, 1H), 4.53-4.47 (m, 1H), 4.38-4.12 (m, 5H), 3.34-3.31 (m, 3H), 2.83-2.72 (m, 1H), 2.40-2.32 (m, 1H), 2.31-1.99 (m, 7H). LCMS R_(T)=0.769 min, m/z=420.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.769 min, ESI+ found [M+H]=420.1

Example 555 WX Method 056

1-[(3,3-dimethylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: (3,3-dimethylcyclobutyl)methanol

To a solution of 3,3-dimethylcyclobutanecarboxylic acid (300 mg, 2.34 mmol) in tetrahydrofuran (10 mL) was added LiAlH₄ (178 mg, 4.68 mmol) at 0° C. The mixture was stirred at 25° C. for 16 h and then quenched by addition of water (0.1 mL), 15% aqueous sodium hydroxide (0.1 mL) and water (0.3 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude (3,3-dimethylcyclobutyl)methanol (100 mg, 86%) as a colorless oil, used as is in the next step.

Step 2: (3,3-dimethylcyclobutyl)methyl 4-methylbenzenesulfonate

To a solution of p-toluenesulfonylchloride (521 mg, 2.73 mmol) in dichloromethane (10 mL) was added (3,3-dimethylcyclobutyl)methanol (260 mg, 2.28 mmol) and 4-dimethylaminopyridine (556 mg, 4.55 mmol). The reaction mixture was stirred at 20° C. for 16 h and then quenched by addition of water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford (3,3-dimethylcyclobutyl)methyl 4-methylbenzenesulfonate (350 mg, 57%) as colorless oil, used as is in the next step.

Step 3: 3-(bromomethyl)-1,1-dimethylcyclobutane

To a solution of (3,3-dimethylcyclobutyl)methyl 4-methylbenzenesulfonate (350 mg, 1.30 mmol) in acetone (20 mL) was added lithium bromide (566 mg, 6.52 mmol). The reaction mixture was heated to 70° C. for 2 h and then concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated to afford crude 3-(bromomethyl)-1,1-dimethylcyclobutane (150 mg, 65%) as colorless oil, used as is in the next step.

Step 4: 1-[(3,3-dimethylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 3-(bromomethyl)-1,1-dimethyl-cyclobutane (37 mg, 0.21 mmol), N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (50 mg, 0.17 mmol) and potassium carbonate (72 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 40-70%/0.05% ammonium hydroxide in water) to afford 1-[(3,3-dimethylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (17.2 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.46 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.32-4.24 (m, 4H), 3.34 (s, 3H), 2.86-2.79 (m, 2H), 2.29-2.23 (m, 4H), 1.87-1.82 (m, 2H), 1.67-1.61 (m, 2H), 1.16 (s, 3H), 1.08 (s, 3H). LCMS R_(T)=0.810 min; m/z=386.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.810 min, ESI+ found [M+H]=386.1.

Example 556 WX Method 169

7,7-dimethyl-6,6-dioxo-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5H-thieno[3,4-d]pyrimidine-2-carboxamide

Step: 2-chloro-7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine

To a mixture of 2,4-dichloro-7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine (1.0 g, 4.25 mmol) and zinc (834 mg, 12.76 mmol) in water (20 mL) was heated at 100° C. for 12 h. The reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL), brine (1×100 mL), dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 2-chloro-7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine (400 mg, 47%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ8.60 (s, 1H), 4.18 (s, 2H), 1.69 (s, 6H).

Step 2: 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carbonitrile

To a solution of 2-chloro-7,7-dimethyl-5H-thieno[3,4-d]pyrimidine (250 mg, 1.25 mmol) in dimethyl sulfoxide (10 mL) and water (10 mL) were added sodium cyanide (122 mg, 2.49 mmol) and 1,4-diazabicyclo[2.2.2]octane (28 mg, 0.25 mmol). The reaction mixture was stirred at 30° C. for 12 h and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 7,7-dimethyl-5H-thieno[3,4-d]pyrimidine-2-carbonitrile (150 mg, 63%) as a white solid.

Step 3: methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate

A solution of 7,7-dimethyl-5H-thieno[3,4-d]pyrimidine-2-carbonitrile (110 mg, 0.58 mmol) in methanol (5 mL) was added HCl (4N in methanol, 5 mL). The mixture was stirred at 25° C. for 12 h and concentrated under reduce pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, 0% to 60% ethyl acetate in petroleum ether) to give methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate (120 mg, 93%) as a white solid. LCMS R_(T)=0.600 min, m/z=224.9 [M+H]⁺.

LCMS (5-95% acetonitrile in water+0.1% trifluoroacetic over 1.5 mins) retention time 0.600 min, ESI+ found [M+H]⁺=224.9

Step 4: methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate 6,6-dioxide

A mixture of oxone (658 mg, 1.07 mmol) and methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate (120 mg, 0.54 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred at 20° C. for 12 h and quenched by addition of saturated sodium hydrogen sulfite (5 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, 0% to 60% ethyl acetate in petroleum ether) to give methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate 6,6-dioxide (120 mg, 88%) as a white solid. LCMS R_(T)=1.226 min, m/z=257.1 [M+H]⁺.

LCMS (0-60% acetonitrile in water+0.1% trifluoroacetic over 2.0 mins) retention time 1.226 min, ESI+ found [M+H]⁺=257.1

Step 5: 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylic acid 6,6-dioxide

A mixture of methyl 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylate 6,6-dioxide (30 mg, 0.12 mmol) and lithium hydroxide (61 mg, 21.9 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred at 25° C. for 16 h. The mixture was adjusted to pH to 5 by addition of hydrochloric acid (1.0 M). The resulting solution was concentrated to dryness under reduced pressure to give crude 7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-2-carboxylic acid 6,6-dioxide (28 mg, 97%) as a white solid, used as is in the next step.

Step 6: 7,7-dimethyl-6,6-dioxo-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5H-thieno[3,4-d]pyrimidine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (22 mg, 0.12 mmol), 7,7-dimethyl-6,6-dioxo-5H-thieno[3,4-d]pyrimidine-2-carboxylic acid (28 mg, 0.12 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (17 mg, 0.13 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (24 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 28% to 58%/0.1% ammonia hydroxide in water) to give 7,7-dimethyl-6,6-dioxo-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5H-thieno[3,4-d]pyrimidine-2-carboxamide (7 mg, 15%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.93 (s, 1H), 7.45-7.43 (m, 1H), 7.36-7.22 (m, 3H), 5.06-5.02 (m, 1H), 4.87-4.86 (m, 2H), 4.66-4.58 (m, 1H), 4.47-4.42 (m, 1H), 3.43 (s, 3H), 1.68 (s, 6H). LCMS R_(T)=1.543 min; m/z=417.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.543 min, ESI+ found [M+H]=417.1.

Example 557 WX Method 085

1-benzyl-N-(1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl)-1,2,4-triazole-3-carboxamide

Step 1: ethyl 4-(5-amino-1H-imidazol-1-yl)butanoate

A mixture solution of ethyl 4-(5-nitroimidazol-1-yl)butanoate (13.0 g, 57.21 mmol) and Pd/C (10%, 5.0 g, 4.7 mmol) in 1,4-dioxane (200 mL) was hydrogenated (25 psi) for 15 h and filtered. The filtrate was concentrated under reduced pressure to afford crude ethyl 4-(5-aminoimidazol-1-yl)butanoate (10 g, 88%) as a black oil, used as is in the next step.

Step 2: 4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

A mixture of ethyl 4-(5-aminoimidazol-1-yl)butanoate (10.0 g, 50.7 mmol) and potassium 2-methylpropan-2-olate (11.38 g, 101.4 mmol) in dimethyl sulfoxide (20 mL) was stirred at 25° C. for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 1,3,4,5-tetrahydroimidazo[1,5-a][1,3]diazepin-2-one (8.0 g, 100%) as a light yellow oil, used as is in the next step.

Step 3: 1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 1,3,4,5-tetrahydroimidazo[1,5-a][1,3]diazepin-2-one (3.0 g, 19.85 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (6.5 g, 19.85 mmol) and iodomethane (2.8 g, 19.85 mmol). The reaction mixture was stirred at 25° C. for 15 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (2.5 g, 76%) as a light yellow oil, used as is in the next step.

Step 4: 9-chloro-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (1.0 g, 6.05 mmol) in chloroform (20 mL) was added 1-chloropyrrolidine-2,5-dione (0.73 g, 5.45 mmol). The reaction mixture was heated at 60° C. for 1 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 9-chloro-1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (1.0 g, 83%) as a light yellow solid, used as is in the next step.

Step 5: 7-bromo-9-chloro-1-methyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 9-chloro-1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (500 mg, 2.5 mmol) in chloroform (20 mL) was added 1-bromo-2,5-pyrrolidinedione (446 mg, 2.5 mmol). The reaction mixture was heated at 60° C. for 4 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% ethyl acetate in petroleum ether) to afford 7-bromo-9-chloro-1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (650 mg, 93%) as a yellow solid, used as is in the next step.

Step 6: 9-chloro-1,7-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

A mixture of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (496 mg, 3.95 mmol) cesium carbonate (1287 mg, 3.95 mmol), PdCl₂(dppf) (144 mg, 0.20 mmol) and 7-bromo-9-chloro-1-methyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (550 mg, 1.97 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 110° C. for 4 h under nitrogen protection. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 9-chloro-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (300 mg, 71%) as a yellow solid, used as is in the next step.

Step 7: 9-chloro-3-iodo-1,7-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 9-chloro-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (250 mg, 1.17 mmol) in dichloromethane (20 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (816 mg, 7.02 mmol) and iodotrimethylsilane (1.4 g, 7.02 mmol) at −15° C. The reaction mixture was stirred at −15° C. for 2 h and iodine (3.56 g, 14.04 mmol) was added. The mixture was stirred at −15° C. for another 2 h and then quenched by addition of 5% aqueous sodium thiosulfate (10 mL). The solution was extracted with dichloromethane (3×20 mL).

The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford 9-chloro-3-iodo-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (300 mg, 75%) as a colorless solid, used as is in the next step.

Step 8: 3-azido-9-chloro-1,7-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

A mixture of 9-chloro-3-iodo-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (300 mg, 0.88 mmol) and sodium azide (500 mg, 7.69 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 2 h and then poured into ice water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.6) to afford 3-azido-9-chloro-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (250 mg, 100%) as a yellow oil, used as is in the next step.

Step 9: 3-amino-1,7-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

A mixture of 3-azido-9-chloro-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (50 mg, 0.20 mmol) and Pd/C (10%, 208 mg, 0.20 mmol) in 1,4-dioxane (5 mL) was hydrogenated (15 psi) for 5 h and filtered. The filtrate was concentrated under reduced pressure to afford 3-amino-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (10 mg, 26%) as a colorless oil, used as is in the next step.

Step 10: 1-benzyl-N-(1,7-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (10.0 mg, 0.05 mmol) 3-amino-1,7-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (10.0 mg, 0.05 mmol), 1-benzo[d][1,2,3]triazol-1-ol (7.0 mg, 0.05 mmol) and 3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (9.9 mg, 0.050 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by RP-HPLC (13% to 43% acetonitrile, 0.05% ammonia hydroxide in water) to afford 1-benzyl-N-(1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl)-1,2,4-triazole-3-carboxamide (6.9 mg, 37%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.41-7.27 (m, 5H), 6.80 (s, 1H), 5.48 (s, 2H), 4.40-4.32 (m, 1H), 4.22-4.16 (m, 1H), 3.73-3.71 (m, 1H), 3.24-3.16 (m, 3H), 2.47-2.41 (m, 1H), 2.29 (s, 3H), 2.23-2.20 (m, 1H). LCMS R_(T)=1.705 min, m/z=380.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.705 ESI+ found [M+H]=380.2.

Example 558 WX Method 151

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine

A mixture of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 12.9 mmol), cesium carbonate (8.4 g, 25.9 mmol), 4-bromotetrahydro-2H-pyran (3.2 g, 19.4 mmol) and sodium iodide (193 mg, 1.3 mmol) in N,N-dimethylformamide (40 mL) was heated at 50° C. for 20 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 10%) as a white solid. LCMS R_(T)=1.024 min; m/z=239.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.024 min, ESI+ found [M+H]=239.1.

Step 2: 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

To a solution of 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.26 mmol) in dimethyl sulfoxide (10 mL) was added 1,4-diazabicyclo[2.2.2]octane (14 mg, 0.13 mmol) and sodium cyanide (180 mg, 3.67 mmol) in water (1 mL). The mixture was stirred at 25° C. for 3 h and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (40% ethyl acetate in petroleum ether) to give 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (100 mg, 35%) as a yellow solid, used as is in the next step.

Step 3: methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

A solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (100 mg, 0.44 mmol) in methanol (5 mL) was added HCl (4N in methanol, 1.5 mL). The mixture was stirred at 20° C. for 20 h and 50° C. for 3 h. The reaction solution was concentrated under reduced pressure to give crude methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (100 mg, 87%) as a yellow solid. LCMS R_(T)=0.930 min; m/z=263.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.930 min, ESI+ found [M+H]=263.2.

Step 4: 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

A mixture of methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (100 mg, 0.38 mmol) and lithium hydroxide hydrate (80 mg, 1.91 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 25° C. for 2 h. The organic solvent was evaporated under reduced pressure and the aqueous phase was adjusted to pH=4 by addition of 2N HCl. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure to give crude 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (60 mg, 63%) as a yellow solid. LCMS R_(T)=0.788 min; m/z=249.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.788 min, ESI+ found [M+H]=249.2.

Step 5: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidine-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (33 mg, 0.17 mmol), 1-tetrahydropyran-4-ylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 0.12 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (36 mg, 0.19 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (25 mg, 0.19 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 20% to 50%/0.05% ammonia hydroxide in water) to give N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-4-yl-pyrazol o[3,4-d]pyrimidine-6-carboxamide (37.61 mg, 73%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 9.14 (d, J=6.4 Hz, 1H), 8.54 (s, 1H), 7.54-7.52 (m, 1H), 7.35-7.28 (m, 3H), 5.17-5.10 (m, 1H), 4.90-4.79 (m, 1H), 4.62-4.50 (m, 2H), 4.03-4.00 (m, 2H), 3.62-3.56 (m, 2H), 3.34 (s, 3H), 2.24-2.15 (m, 2H), 1.94-1.91 (m, 2H). LCMS R_(T)=0.762 min; m/z=423.1 (M+H)⁺.

LCMS (5-95% acetonitrile in water+0.05% trifluoacetic acid over 1.5 mins) retention time 0.762 min, ESI+ found [M+H]=423.1.

Example 559

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 149. The crude was purified by RP-HPLC (acetonitrile 17% to 47%/0.05% ammonia hydroxide in water) to give N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-tetrahydro pyran-4-yl-pyrazolo[3,4-d]pyrimidine-6-carboxamide (38.5 mg, 74%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ9.47 (s, 1H), 9.16 (d, J=8.0 Hz, 1H), 8.53 (s, 1H), 6.16 (s, 1H), 5.19-5.15 (m, 1H), 4.43-4.40 (m, 1H), 4.29-4.25 (m, 1H), 4.21-4.11 (m, 1H), 4.04-3.99 (m, 2H), 3.63-3.56 (m, 2H), 3.25 (s, 3H), 2.74-2.69 (m, 1H), 2.50-2.49 (m, 1H), 2.22-2.18 (m, 5H), 1.94-1.91 (m, 2H). LCMS R_(T)=0.705 min; m/z=425.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.792 min, ESI+ found [M+H]=425.1.

Example 560 WX Method 057

1-[(1-methylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: (1-methylcyclobutyl)methanol

To a solution of 1-methylcyclobutanecarboxylic acid (300 mg, 2.63 mmol) in tetrahydrofuran (10 mL) was added LiAlH₄ (249 mg, 6.57 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 h and then quenched by addition of water (1.0 mL) and 15% aqueous sodium hydroxide (0.3 mL). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude (1-methylcyclobutyl)methanol (260 mg, 99%) as colorless oil, used as is in the next step.

Step 2: (1-methylcyclobutyl)methyl 4-methylbenzenesulfonate

To a solution of 4-dimethylaminopyridine (634 mg, 5.19 mmol) in dichloromethane (10 mL) was added p-toluenesulfonylchloride (594 mg, 3.12 mmol) and (1-methylcyclobutyl)methanol (260 mg, 2.60 mmol). The reaction mixture was stirred at 20° C. for 16 h and then quenched by addition of water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford (1-methylcyclobutyl)methyl 4-methylbenzenesulfonate (500 mg, 76%) as colorless oil, used as is in the next step.

Step 3: 1-(bromomethyl)-1-methylcyclobutane

A mixture of lithium bromide thium (598 mg, 6.88 mmol) and (1-methylcyclobutyl)methyl 4-methylbenzenesulfonate (350 mg, 1.38 mmol) in acetone (15 mL) was heated to 70° C. for 4 h. After cooled, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (10 mL), brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 1-(bromomethyl)-1-methyl-cyclobutane (120 mg, 54%) as yellow oil, used as is in the next step.

Step 4: 1-[(1-methylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (30 mg, 0.10 mmol), 1-(bromomethyl)-1-methyl-cyclobutane (25 mg, 0.16 mmol) and potassium carbonate (43 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to afford 1-[(1-methylcyclobutyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (7.5 mg, 13%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 6.12 (s, 1H), 4.57-4.52 (m, 1H), 4.35-4.23 (m, 4H), 3.34 (s, 3H), 2.91-2.87 (m, 1H), 2.29-2.26 (m, 4H), 2.13-2.08 (m, 2H), 1.96-1.92 (m, 1H), 1.87-1.83 (m, 1H), 1.77-1.72 (m, 2H), 1.10 (s, 3H). LCMS R_(T)=0.637 min; m/z=372.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.637 min, ESI+ found [M+H]=372.0.

Example 561

1-[(1-methylcyclobutyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 057. The crude was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give 1-[(1-methylcyclobutyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (12 mg, 17%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.49 (s, 1H), 6.01 (s, 1H), 4.56-4.51 (m, 1H), 4.32-4.21 (m, 4H), 3.32 (s, 3H), 2.89-2.83 (m, 1H), 2.28-2.24 (m, 1H), 2.12-2.08 (m, 2H), 1.95-1.90 (m, 3H), 1.77-1.73 (m, 2H), 1.10 (s, 3H), 0.95-0.93 (m, 2H), 0.74-0.72 (m, 2H). LCMS R_(T)=0.727 min; m/z=398.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.727 min, ESI+ found [M+H]=398.0.

Example 562 WX Method 136

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxamide

Step 1: 1-[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]cyclopentanol

To a solution of 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2 g, 5.6 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h then a solution of cyclopentanone (1.2 g, 14.3 mmol) in tetrahydrofuran (2 mL) was added dropwise. After addition, the reaction mixture was stirred at −78° C. for 1 h and quenched by addition of saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford 1-[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]cyclopentanol (1.5 g, 72%) as a colorless oil. LCMS R_(T)=0.790 min, m/z=361.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.790 min, ESI+ found [M+H]=361.8

Step 2: 1-[5-bromo-2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]cyclopentanol

To a solution of 1-[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]cyclopentanol (200 mg, 0.56 mmol) in methanol (10 mL) was added p-toluenesulfonic acid (191 mg, 1.11 mmol). The mixture was stirred at 20° C. for 2 h and concentrated under reduced pressure to afford crude 1-[5-bromo-2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]cyclopentanol (250 mg, 110%) as a colorless oil. LCMS R_(T)=0.423 min, m/z=275.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.423 min, ESI+ found [M+H]=275.9

Step 3: 2-[3-bromo-5-(1-hydroxycyclopentyl)-1,2,4-triazol-1-yl]ethyl 4-methyl benzenesulfonate

A mixture of 1-[5-bromo-2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]cyclopentanol (250 mg, 0.91 mmol), 4-dimethylaminopyridine(11 mg, 0.09 mmol), trimethylamine (0.63 mL, 4.53 mmol) and p-toluenesulfonyl chloride (190 mg, 1 mmol) in dichloromethane (5 mL) was stirred at 19° C. for 4 h. The mixture concentrated under reduced pressure and the residue was purified by preparative TLC (ethyl acetate: petroleum ether=1:3, R_(f)=0.6) to give 2-[3-bromo-5-(1-hydroxycyclopentyl)-1,2,4-triazol-1-yl]ethyl4-methylbenzenesulfonate (180 mg, 46%) as colorless oil, used as is in the next step.

Step 4: 2-bromospiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]

To a solution of 2-[3-bromo-5-(1-hydroxycyclopentyl)-1,2,4-triazol-1-yl]ethyl 4-methylbenzenesulfonate (180 mg, 0.420 mmol) in tetrahydrofuran (40 mL) was added lithium bis(trimethylsilyl)amide (1.0 N in tetrahedron, 0.84 mL, 0.84 mmol) at −70° C. The mixture was stirred at −70° C. for 1 h and then allowed to warm to 20° C. over 12 h. The reaction mixture was quenched by addition of water (5 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (33% ethyl acetate in petroleum ether, R_(f)=0.5) to afford 2-bromospiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8, 1′-cyclopentane] (70 mg, 65%) as a yellow solid. LCMS R_(T)=0.646 min, m/z=257.7 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.646 min, ESI+ found [M+H]=257.7

Step 5: ethyl spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxylate

A mixture of 2-bromospiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8, 1,1′-cyclopentane](60 mg, 0.23 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (17 mg, 0.02 mmol) and triethylamine (0.26 mL, 2.32 mmol) in methanol (20 mL) was heated at 70° C. under CO (35 psi) for 20 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (ethyl acetate: petroleum ether=1:2, R_(f)=0.3) to afford methyl spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxylate (52 mg, 89%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ4.30-4.25 (m, 2H), 4.16-4.10 (m, 2H), 3.94 (s, 3H), 2.19-2.07 (m, 4H) 1.95-1.84 (m, 4H). LCMS R_(T)=0.602 min, m/z=237.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 0.602 min, ESI+ found [M+H]=237.8

Step 6: spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxylic acid

A mixture of methyl spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxylate (52 mg, 0.22 mmol) and lithium hydroxide (16 mg, 0.66 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was stirred at 18° C. for 2 h. The mixture was adjusted to pH=3 by addition of 1N HCl. The mixture was concentrated under reduced pressure to give crude spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8, 1′-cyclopentane]-2-carboxylic acid (48 mg, 98%) as a colorless oil. LCMS R_(T)=0.514 min, m/z=223.8 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.514 min, ESI+ found [M+H]=223.8

Step 7: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxamide

A mixture of spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxylic acid (24 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (33 mg, 0.22 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (21 mg, 0.11 mmol) and 1-hydroxybenzotriazole (29 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL) was stirred at 20° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (40% to 70% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxamide (24.2 mg, 57%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.45-7.42 (m, 1H), 7.32-7.30 (m, 2H), 7.25-7.23 (m, 1H), 5.02-5.00 (m, 1H), 4.62-4.58 (m, 1H), 4.45-4.41 (m, 1H), 4.27-4.25 (m, 2H), 4.13-4.11 (m, 2H), 3.42 (s, 3H), 2.16-2.14 (m, 4H), 1.91-1.90 (m, 4H). LCMS R_(T)=0.807 min, m/z=398.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.807 min, ESI+ found [M+H]=398.1

Example 563 WX Method 146

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: 6-chloro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine

To a solution of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 6.47 mmol), triphenylphosphine (2.5 g, 9.7 mmol) and tetrahydro-2h-pyran-3-ol (661 mg, 6.47 mmol) in tetrahydrofuran (5 ml) was added diisopropyl azodicarboxylate (1.9 g, 9.7 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL), dried over magnesium sulfate and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 6-chloro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.5 g, 97%) as a white solid. LCMS R_(T)=1.07 min, m/z=239.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 1.07 min, ESI+ found [M+H]=239.2.

Step 2: 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

To a solution of 6-chloro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.09 mmol) in dimethyl sulfoxide (20 mL) was added sodium cyanide (205 mg, 4.19 mmol) in water (10 mL). The mixture was heated at 40° C. for 3 h and diluted with water (100 mL). The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed brine (50 mL), dried over magnesium sulfate and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (120 mg, 25%) as a yellow oil, used as is in the next step.

Step 3: methyl 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

A solution of 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (120 mg, 0.52 mmol) in methanol (10 mL) was added HCl (4N in methanol, 3 mL). The mixture was stirred at 50° C. for 24 h and concentrated under reduced pressure to give methyl 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (110 mg, 80%) as a yellow solid. LCMS R_(T)=0.97 min, m/z=263.3 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.97 min, ESI+ found [M+H]=263.3.

Step 4: 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

A mixture of methyl 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (100 mg, 0.38 mmol) and lithium hydroxide (46 mg, 1.91 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 25° C. for 4 h. The organic solvent was removed under reduced pressure and the aqueous residue was adjusted to pH=2 by addition of 1N HCl. The mixture was extracted with ethyl acetate (2×20 mL). The combined organics were concentrated under reduced pressure to give crude 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (70 mg, 74%) as a white solid, used as is in the next step. LCMS R_(T)=0.85 min, m/z=249.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.85 min, ESI+ found [M+H]=249.2.

Step 5: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidine-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mmol), 1-tetrahydropyran-3-ylpyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 0.12 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (35 mg, 0.18 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (25 mg, 0.19 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 50% to 80%/0.05% ammonia hydroxide in water) to give N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-tetrahydropyran-3-yl-pyrazol o[3,4-d]pyrimidine-6-carboxamide (14.0 mg, 27%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 9.36 (s, 1H), 8.38 (s, 1H), 7.47-7.44 (m, 1H), 7.34-7.27 (m, 3H), 5.17-5.11 (m, 2H), 4.75-4.65 (m, 1H), 4.58-4.40 (m, 1H), 4.15-3.85 (m, 3H), 3.65-3.53 (m, 1H), 3.45 (s, 3H), 2.40-2.33 (m, 1H), 2.25-2.21 (m, 1H), 1.98-1.91 (m, 2H). LCMS R_(T)=0.70 min, m/z=423.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.70 min, ESI+ found [M+H]=423.0.

Example 564

7-methyl-7-propyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method N. The crude was purified by RP-HPLC (acetonitrile 26% to 56%/0.05% ammonia hydroxide in water) 7-methyl-7-propyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide (43 mg,41%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.82 (s, 1H), 6.13 (s, 1H), 5.20-5.12 (m, 2H), 4.62-4.55 (m, 1H), 4.37-4.21 (m, 2H), 3.36 (s, 3H), 3.00-2.90 (m, 1H), 2.31-2.25 (m, 4H), 1.95-1.79 (m, 2H), 1.49-1.40 (m, 4H), 1.08-0.95 (m, 1H), 0.87 (t, J=6.8 Hz, 3H). LC-MS R_(T)=1.546 min, m/z=395.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide over 3.0 mins) retention time 1.546 min, ESI+ found [M+H]=395.2.

Example 565

N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo [3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 136. The crude was purified by RP-HPLC (17% to 47% acetonitrile/0.05% ammonia hydroxide in water) to give N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide (35.6 mg, 41%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.79 (s, 1H), 7.54 (s, 1H), 6.32 (s, 1H), 5.11 (s, 2H), 4.59-4.57 (m, 1H), 4.55-4.43 (m, 1H), 4.33-4.31 (m, 1H), 3.38 (s, 3H), 3.00-2.95 (m, 1H), 2.33-2.28 (m, 1H), 2.07-2.03 (m, 4H), 1.94-1.92 (m, 4H). LC-MS R_(T)=0.720 min, m/z=383.1 [M+H].

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.720 min, ESI+ found [M+H]=383.1.

Example 566

7-methyl-7-propyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method N. The crude was purified by RP-HPLC (19% to 49% acetonitrile/0.05% ammonia hydroxide in water) to afford 7-methyl-7-propyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide (32.6 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.82 (s, 1H), 7.55 (d, J=2.4 Hz, 1H), 6.33 (s, 1H), 5.20-5.12 (m, 2H), 4.60-4.55 (m, 1H), 4.49-4.43 (m, 1H), 4.36-4.28 (m, 1H), 3.39 (s, 3H), 3.03-2.92 (m, 1H), 2.35-2.28 (m, 1H), 1.96-1.79 (m, 2H), 1.49-1.40 (m, 4H), 1.08-0.95 (m, 1H), 0.87 (t, J=6.8 Hz, 3H). LC-MS R_(T)=1.473 min, m/z=385.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide over 3.0 mins) retention time 1.473 min, ESI+ found [M+H]=385.2.

Example 567

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 136. The crude was purified by RP-HPLC (13% to 43% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5,6-dihydro-[1,2,4]triazolo[5,1-c][1,4]oxazine-8,1′-cyclopentane]-2-carboxamide (32.9 mg, 77%), as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=7.2 Hz, 1H), 6.13 (s, 1H), 4.40-4.20 (m, 4H), 4.16-4.03 (m, 3H), 3.22 (s, 3H), 2.63-2.54 (m, 1H), 2.39-2.30 (m, 1H), 2.17 (s, 3H), 2.11-1.96 (m, 4H), 1.87-1.43 (m, 4H). LCMS R_(T)=0.724 min, m/z=400.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 0.724 min, ESI+ found [M+H]=400.1

Example 568 WX Method 118

8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

Step 1: ethyl N-[(3-bromo-2-pyridyl)carbamothioyl]carbamate

To a solution of 3-bromo-2-pyridinamine (10.0 g, 57.8 mmol) in 1,4-dioxane (50 mL) was added ethoxycarbonyl isothiocyanate (9.1 g, 69.4 mmol). The reaction mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The resulting solid was triturated in ether, filtered and dried to give crude ethyl N-[(3-bromo-2-pyridyl)carbamothioyl]carbamate (10.6 g, 60%) as a pale yellow solid. LCMS R_(T)=0.728 min, m/z=305.7 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.728 min, ESI+ found [M+H]=305.7

Step 2: 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a solution of N,N-diisopropylethylamine (13.51 g, 104.53 mmol) in methanol (300 mL) and ethanol (30 mL) was added hydroxylamine hydrochloride (12.11 g, 174.27 mmol). The mixture was stirred at 25° C. for 30 min and then ethyl N-[(3-bromo-2-pyridyl)carbamothioyl]carbamate (10.6 g, 34.85 mmol) was added. The resulting mixture was heated at 65° C. for 16 h and concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (30 mL) and filtered. The filtrate was washed with water (30 mL), dried over sodium sulfate and concentrated to give crude 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (4.1 g, 55%) as a white solid, used as is in the next step.

Step 3: 8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (4.1 g, 19.25 mmol), phenylboronicacid (3.52 g, 28.87 mmol), tetrakis(triphenylphosphine)palladium(0) (2.22 g, 1.92 mmol) and sodium bicarbonate (4.85 g, 57.73 mmol) in 1,4-dioxane (35 mL) and water (7 mL) was heated at 150° C. for 10 min under microwave conditions. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (300 mL) and filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% ethyl acetate in petroleum ether) to afford 8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.0 g, 74%) as a yellow solid, used as is in the next step. LCMS R_(T)=0.593 min, m/z=210.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.593 min, ESI+ found [M+H]=210.9.

Step 4: 2-iodo-8-phenyl-[1,2,4]triazolo[1,5-a]pyridine

To a suspension of 8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (100 mg, 0.48 mmol) and p-toluenesulfonicacid monohydrate (343 mg, 1.81 mmol) in acetonitrile (8 mL) was added an solution of potassium iodide (261 mg, 1.57 mmol) and sodium nitrite (82 mg, 1.19 mmol) in water (2 mL) at 13° C. After addition, the reaction mixture was stirred at 13° C. for 10 hand then diluted with ethyl acetate (20 mL). The separated organic layer was washed with water (2×10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue which was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to afford 2-iodo-8-phenyl-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 65%) as a yellow solid, used as is in the next step. LCMS R_(T)=0.845 min, m/z=321.8 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.845 min, ESI+ found [M+H]=321.8

Step: 5: 8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

A mixture of 2-iodo-8-phenyl-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 0.09 mmol), (3 s)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (18 mg, 0.09 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01 mmol), triethylamine (61 mg, 0.61 mmol) and palladium diacetate (2 mg, 0.01 mmol) in toluene (2 mL) was heated at 80° C. under CO atmosphere (15 psi) for 5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RR-HPLC (40% to 70% acetonitrile/0.05% ammonia hydroxide in water) to give 8-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (5.7 mg, 9%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.83-8.77 (m, 1H), 8.06 (d, J=7.2 Hz, 2H), 7.94-7.88 (m, 1H), 7.57-7.51 (m, 2H), 7.50-7.42 (m, 2H), 7.40-7.28 (m, 3H), 7.27-7.21 (m, 1H), 5.12-5.04 (m, 1H), 4.67-4.62 (m, 1H), 4.52-4.46 (m, 1H), 3.43 (s, 3H). LCMS R_(T)=0.851 min, m/z=414.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.851 min, ESI+ found [M+H]=414.1

Example 569 WX Method 041

1-[(3,3-difluorocyclopentyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: (3,3-difluorocyclopentyl)methanol

To a mixture of LiAlH₄ (253 mg, 6.66 mmol) in tetrahydrofuran (10 mL) was added 3,3-difluorocyclopentanecarboxylic acid (500 mg, 3.33 mmol) in tetrahydrofuran (4 mL) at 0° C. the reaction mixture was stirred at 25° C. for 18 h and then quenched by addition of water (0.1 mL), 15% aqueous NaOH (0.1 mL) and water (0.3 mL). The resulting mixture was diluted with dichloromethane (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude (3,3-difluorocyclopentyl)methanol (320 mg, 71%) as a colorless oil, used as is in the next step.

Step 2: (3,3-difluorocyclopentyl)methyl 4-methylbenzenesulfonate

To a solution of (3,3-difluorocyclopentyl)methanol (300 mg, 2.20 mmol) in dichloromethane (10 mL) was added 4-dimethylaminopyridine (323 mg, 2.64 mmol) and 4-methylbenzene-1-sulfonyl chloride (504 mg, 2.64 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 18 h and quenched by addition of water (10 mL). The mixture was extracted with dichloromethane (2×20 ml). The combined organic layers were washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford (3,3-difluorocyclopentyl)methyl 4-methylbenzenesulfonate (300 mg, 47%) as a colorless oil, used as is in the next step.

Step 3: 1,1-difluoro-3-(iodomethyl)cyclopentane

A mixture of (3,3-difluorocyclopentyl)methyl 4-methylbenzenesulfonate (100 mg, 0.34 mmol) and sodium iodide (154 mg, 1.03 mmol) in acetone (5 mL) was heated at 40° C. for 18 h and concentrated under reduce pressure. The residue was diluted with ethyl acetate (30 mL) and washed with water (3×20 mL), brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated to give crude 1,1-difluoro-3-(iodomethyl)cyclopentane (84 mg, 99%) as a 20-colorless oil, used as is in the next step.

Step 4: 1-[(3,3-difluorocyclopentyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 1,1-difluoro-3-(iodomethyl)cyclopentane (76 mg, 0.31 mmol), N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1H-1,2,4-triazole-3-carboxamide (45 mg, 0.16 mmol) and potassium carbonate (64 mg, 0.47 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction was concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonium hydroxide in water) to afford 1-[(3,3-difluorocyclopentyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1, 5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (14 mg, 22%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.50 (s, 1H), 6.11 (s, 1H), 4.59-4.51 (m, 2H), 4.31-4.27 (m, 2H), 4.26-4.18 (m, 1H), 3.33 (s, 3H), 2.94-2.69 (m, 3H), 2.25 (s, 3H), 2.22-1.84 (m, 5H), 1.63-1.53 (m, 1H). LC-MS R_(T)=1.512 min, m/z=408.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.512 min, ESI+ found [M+H]=408.2.

Example 570 WX Method 083

1-benzyl-N-(6S)-2-(1-fluorocyclopropyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: butyl 1-fluorocyclopropanecarboxylate

A solution of 1-fluorocyclopropanecarboxylic acid (6.00 g, 57.65 mmol) in acetonitrile (60 mL) was added DBU (9.65 g, 63.41 mmol) and 1-iodobutane (11.67 g, 63.41 mmol) dropwise at 0° C. The resulting mixture was stirred at 25° C. for 12 h and quenched by addition of water (100 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude butyl 1-fluorocyclopropanecarboxylate (7.5 g, 81%) as a yellow oil, used as is in the next step.

Step 2: 3-(1-fluorocyclopropyl)-3-oxopropanenitrile

To a solution of acetonitrile (3.0 mL, 51.5 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M in hexane, 21.0 mL, 51.5 mmol) dropwise at −78° C. The resulting mixture was stirred at the same temperature for 30 minutes and butyl 1-fluorocyclopropanecarboxylate (7.5 g, 46.8 mmol) was added. After addition, the reaction mixture was stirred at room temperature for 2 h and then quenched by addition of saturated ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude 3-(1-fluorocyclopropyl)-3-oxopropanenitrile (3.7 g, 62%) as yellow oil, used as is in the next step.

Step 3: 5-(1-fluorocyclopropyl)-1H-pyrazol-3-amine

A mixture of 3-(1-fluorocyclopropyl)-3-oxopropanenitrile (3.7 g, 29.11 mmol) and hydrazine hydrate (50 mL) in propan-2-ol (30 mL) was heated at 80° C. for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to give 5-(1-fluorocyclopropyl)-1H-pyrazol-3-amine (0.75 g, 18%) as yellow oil. LCMS R_(T)=0.95 min, m/z=142.1 [M+H]⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3 minutes) retention time 0.95 min, ESI+ found [M+H]=142.1.

Step 4: N-(5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl)formamide

A mixture of 5-(1-fluorocyclopropyl)-1H-pyrazol-3-amine (750 mg, 5.31 mmol) and formic acid (15 mL) was heated at 110° C. for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to give N-[5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl]formamide (600 mg, 67%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ12.69 (br. s, 1H), 10.56 (br. s, 1H), 8.15 (s, 1H), 6.46 (s, 1H), 1.45-1.36 (m, 2H), 1.09-1.07 (m, 2H).

Step 5: 5-(1-fluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine

To a stirred solution of N-[5-(1-fluoocyclopropyl)-1H-pyrazol-3-yl]formamide (600 mg, 3.55 mmol) in tetrahydrofuran (10 mL) was added borane (10 M in Me₂S, 1.8 mL, 18.0 mmol) at 0° C. After addition, the mixture was stirred for 2 h at 0° C. and then quenched by addition of methanol (10 mL). The mixture was stirred for 30 min and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to obtain 5-(1-fluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (380 mg, 69%) as a yellow oil. LCMS R_(T)=1.44 min, m/z=156.1 [M+H]⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3.0 mins) retention time 1.44 min, ESI+ found [M+H]=156.1.

Step 6: 4-chloro-N-(5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl)-N-methylbutanamide

A mixture of 5-(1-fluorocyclopropyl)-N-methyl-1H-pyrazol-3-amine (380 mg, 2.45 mmol) and 4-chlorobutanoyl chloride (2 mL) was heated at 60° C. for 2.5 h and then quenched by addition of methanol (10 mL). The mixture was stirred for 30 mn and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 4-chloro-N-[5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (450 mg, 70%) as a yellow oil. LCMS R_(T)=0.75 min, m/z=259.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.75 min, ESI+ found [M+H]=259.9.

Step 7: 2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 4-chloro-N-[5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (400 mg, 1.54 mmol) and cesium carbonate (1.0 g, 3.08 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (180 mg, 52%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.09 (s, 1H), 4.19-4.15 (m, 2H), 3.24 (s, 3H), 2.42-2.35 (m, 2H), 2.34-2.25 (m, 2H), 1.41-1.31 (m, 2H), 1.12-1.04 (m, 2H).

Step 8: 2-(1-fluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5a][1,3]diazepin-5(6H)-one

To a stirred solution of 2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (180 mg, 0.81 mmol) in dichloromethane (15 mL) was added N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (937 mg, 8.06 mmol) and iodotrimethylsilane (1.6 g, 8.06 mmol) at −15° C. The mixture was stirred at −15° C. for 1.5 h, then iodine (614 mg, 2.42 mmol) was added. The mixture was stirred for another 3 h and then quenched by addition of 50% aqueous sodium thiosulfate (10 mL). The mixture was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 2-(1-fluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (150 mg, 53%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.13 (s, 1H), 4.58-4.54 (m, 1H), 4.19-4.10 (m, 2H), 3.29 (s, 3H), 2.94-2.83 (m, 1H), 2.75-2.65 (m, 1H), 1.39-1.32 (m, 2H), 1.12-1.02 (m, 2H). LCMS R_(T)=2.07 min, m/z=350.0 [M+H]⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 2.07 min, ESI+ found [M+H]=350.0.

Step 9: 6-azido-2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 2-(1-fluorocyclopropyl)-6-iodo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (150 mg, 0.43 mmol) and sodium azide (57 mg, 0.87 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 12 h. The reaction mixture was quenched by addition of 20% aqueous sodium hypochlorite (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-azido-2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (105 mg, 93%) as a yellow oil.

Step 10: 6-amino-2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of 6-azido-2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (60 mg, 0.23 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 80% polymer-bound triphenylphosphine (357 mg). The reaction mixture was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 6-amino-2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 92%) as a light yellow oil.

LCMS R_(T)=1.48 min, m/z=239.1 [M+H]⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.48 min ESI+ found [M+H]=239.1.

Step 11: 1-benzyl-N-(6S)-2-(1-fluorocyclopropyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (51 mg, 0.25 mmol), 6-amino-2-(1-fluorocyclopropyl)-4-methyl-7,8-dihydro-6H-pyrazolo][1,5-a][1,3]diazepin-5-one (50 mg, 0.21 mmol), N,N-dimethyl-3 (methyliminomethylenethylacetatemino) propan-1-amine hydrochloride (56 mg, 0.31 mmol) and 1-hydroxybenzotrizole (43 mg, 0.31 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (0% to 40% acetonitrile, 0.05% ammonia hydroxide in water) to afford 1-benzyl-N-2-(1-fluorocyclopropyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (60 mg, 67%) as a white solid. This material was separated by chiral SFC to give:

1-benzyl-N-(6S)-2-(1-fluorocyclopropyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time 3.77 min) (8 mg, 13%) as white solids. ¹H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.41-7.28 (m, 5H), 6.37 (s, 1H), 5.46 (s, 2H), 4.56-4.53 (m, 1H), 4.39-4.31 (m, 1H), 4.29-4.20 (m, 1H), 3.34 (s, 3H), 2.84 (m, 1H), 2.26 (m, 1H), 1.42-1.34 (m, 2H), 1.18-1.07 (m, 2H). LCMS RT=1.672 min, m/z=424.2 (M+H)+.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.672 min, ESI+ found [M+H]=424.2

SFC conditions: Column: Chiralcel AD-3 50×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min. Flow rate: 4.0 mL/min Column temperature: 40° C.)

Examples 571, 572 and 573 WX Method 115

7-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (7S)-7-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (7R)-7-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 113 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by PR-HPLC (22% to 52% acetonitrile, 0.05% ammonia hydroxide in water) to afford 7-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (5.5 mg, 26%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.41 (m, 1H), 7.39-7.26 (m, 7H), 7.25-7.21 (m, 1H), 5.02-4.97 (m, 1H), 4.60-4.52 (m, 2H), 4.45-4.35 (m, 2H), 4.32-4.22 (m, 1H), 3.40 (s, 3H), 3.28-3.23 (m, 1H), 2.76-2.67 (m, 1H). LCMS R_(T)=1.017 min, m/z=404.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.017 min, ESI+ found [M+H]=404.3.

Another Batch of the Racemic Material (60 mg) was Separated by Chiral SFC to Give:

(7S)-7-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 1, retention time=3.325 min) (18.3 mg, 30%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ7.42-7.22 (m, 9H), 5.00-4.87 (m, 1H), 4.61-4.53 (m, 2H), 4.42-4.39 (m, 2H), 4.37-4.28 (m, 1H), 3.40 (s, 3H), 3.28-3.25 (m, 1H), 2.76-2.70 (m, 1H). LCMS R_(T)=1.011 min, m/z=404.4 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.011 min, ESI+ found [M+H]=404.4.

(7R)-7-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 2, retention time=3.439 min) (16.1 mg, 27%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ7.41-7.24 (m, 9H), 5.00-4.97 (m, 1H), 4.60-4.54 (m, 2H), 4.42-4.39 (m, 2H), 4.37-4.28 (m, 1H), 3.41 (s, 3H), 3.28-3.25 (m, 1H), 2.76-2.69 (m, 1H). LCMS R_(T)=1.006 min, m/z=404.4 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.006 min, ESI+ found [M+H]=404.4.

SFC condition: Column: Chiralcel IC-3 150×4.6 mm I.D., 3 um Mobile phase: 40% iso-propanol (0.05% DEA) in CO₂ Flow rate: 2.5 mL/min Column temperature: 40° C.

Examples 574 and 575

7-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (7S)-7-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 113 (RIP1K_experimental_3^(rd) WX.doc). The crude was purified by PR-HPLC (22% to 52% acetonitrile/0.05% ammonia hydroxide in water) to afford 7-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (6.2 mg, 29%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ7.39-7.25 (m, 5H), 6.11 (s, 1H), 4.57-4.49 (m, 2H), 4.45-4.36 (m, 1H), 4.35-4.15 (m, 3H), 3.32 (s, 3H), 3.30-3.24 (m, 1H), 2.90-2.66 (m, 2H), 2.33-2.14 (m, 4H). LCMS R_(T)=0.920 min, m/z=406.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.920 min, ESI+ found [M+H]=406.3.

Another Batch of the Racemic Material (50 mg) was Separated by Chiral SFC to Give:

(7S)-7-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 1, retention time 3.64 min) (22 mg, 44% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ9.35 (s, 1H), 8.38 (s, 1H), 7.05-7.00 (m, 2H), 5.45-5.40 (m, 1H), 4.69-4.64 (m, 1H), 3.05-3.02 (m, 1H), 2.89-2.76 (m, 2H), 2.32-2.26 (m, 1H), 1.60 (d, J=6.8 Hz, 6H). LCMS R_(T)=1.95 min, m/z=406.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.95 min, ESI+ found [M+H]=406.2.

SFC conditions: Column: Chiralcel AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% dethyl acetate), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature:40° C.

Example 576

1-[(2-fluorophenyl)methyl]-N-(3R)-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1, 3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 085. The crude was purified by RP-HPLC (15% to 45% acetonitrile, 0.05% ammonia hydroxide in water) to afford 1-[(2-fluorophenyl)methyl]-N-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (50 mg, 54%) as a white solid. The racemic compound was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-(3R)-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.788 min) (23 mg, 25%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.46-7.39 (m, 1H), 7.38-7.31 (m, 1H), 7.28-7.19 (m, 2H), 6.80 (s, 1H), 5.55 (s, 2H), 4.38-4.33 (m, 1H), 4.23-4.17 (m, 1H), 3.75-3.71 (m, 1H), 3.23-3.17 (m, 3H), 2.47-2.41 (m, 1H), 2.29 (s, 3H), 2.25-2.17 (m, 1H). LCMS R_(T)=1.77 min; m/z=398.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.77 min, ESI+ found [M+H]=398.1

SFC conditions: Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 577

1-[(2,5-difluorophenyl)methyl]-N-(3R)-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 085. The crude was purified by RP-HPLC (18% to 48% acetonitrile, 0.05% ammonia hydroxide in water) to afford 1-[(2,5-difluorophenyl)methyl]-N-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]di azepin-3-yl-1,2,4-triazole-3-carboxamide (50 mg, 52%) as white solids. The racemic compound was separated by chiral SFC to give:

1-[(2,5-difluorophenyl)methyl]-N-(3R)-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.857 min) (17 mg, 17.5%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.50 (d, J=8.0 Hz, 1H), 7.37-7.22 (m, 3H), 6.80 (s, 1H), 5.54 (s, 2H), 4.40-4.32 (m, 1H), 4.22-4.16 (m, 1H), 3.75-3.69 (m, 1H), 3.21 (s, 3H), 2.47-2.41 (m, 1H), 2.29 (s, 3H), 2.25-2.17 (m, 1H). LCMS R_(T)=1.796 min, m/z=416.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.796 min, ESI+ found [M+H]=416.1

SFC conditions: Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 578

1-[(2,6-difluorophenyl)methyl]-N-[(3R)-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 085. The crude was purified by RP-HPLC (20% to 50% acetonitrile, 0.05% ammonia hydroxide in water) to afford 1-[(2,6-difluorophenyl)methyl]-N-(1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]di azepin-3-yl)-1,2,4-triazole-3-carboxamide (50 mg, 47%) as white solids. The racemic compound was separated by chiral SFC to give:

1-[(2,6-difluorophenyl)methyl]-N-[(3R)-1,7-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.519 min) (21 mg, 42%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.54-7.46 (m, 1H), 7.19-7.15 (m, 2H), 6.80 (s, 1H), 5.55 (s, 2H), 4.37-4.30 (m, 1H), 4.21-4.16 (m, 1H), 3.75-3.67 (m, 1H), 3.20 (s, 3H), 2.46-2.40 (m, 1H), 2.29 (s, 3H), 2.24-2.16 (m, 1H). LCMS RT=1.762 min; m/z=416.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.762 min, ESI+ found [M+H]=416.2

SFC conditions: Column Chiralcel OJ-3 150×4.6 mm I.D., 3 um, Mobile phase: A: CO₂ B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 5.0 min and hold 40% for 2.5 min, then 5% of B for 2.5 min, Flow rate: 2.5 mL/min Column temperature: 35° C.

Example 579

7-phenyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 113 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by PR-HPLC (22% to 52% acetonitrile/0.05% ammonia hydroxide in water) to afford 7-phenyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (14.5 mg, 45%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ7.52 (s, 1H), 7.39-7.32 (m, 2H), 7.32-7.25 (m, 3H), 6.30 (s, 1H), 4.57-4.46 (m, 2H), 4.45-4.35 (m, 2H), 4.33-4.20 (m, 2H), 3.35 (s, 3H), 3.30-3.24 (m, 1H), 2.91-2.79 (m, 1H), 2.76-2.66 (m, 1H), 2.32-2.21 (m, 1H). LCMS R_(T)=0.889 min, m/z=392.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.889 min, ESI+ found [M+H]=392.3.

Example 580

1-[(2-fluorophenyl)methyl]-N-[(3R)-1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo 11,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 043. The crude was purified by RP-HPLC (5% to 35% acetonitrile, 0.05% HCl in water) to give N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (70 mg, 68%) as a white solid. This racemic material was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-[(3R)-1,9-dimethyl-2-oxo-4, 5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 3.642 min) (47 mg, 33%).

¹H NMR (400 MHz, CD₃OD) δ8.59 (s, 1H), 7.56 (s, 1H), 7.41-7.38 (m, 2H), 7.22-7.15 (m, 2H), 5.55 (s, 2H), 4.57-4.52 (m, 1H), 4.37-4.31 (m, 1H), 3.96-3.93 (m, 1H), 3.31 (s, 3H), 2.72-2.63 (m, 1H), 2.22 (s, 3H), 2.15-2.09 (m, 1H). LCMS R_(T)=0.447 min; m/z=398.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.447 min, ESI+ found [M+H]=398.0

SFC conditions: Column: Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.8 mL/min Column temp.: 40° C.

Example 581

1-[(2,6-difluorophenyl)methyl]-N-(3R)-1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 100 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by RP-HPLC (5% to 35% acetonitrile, 0.05% HCl in water) to give 1-(2,6-difluorobenzyl)-N-(1,9-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (70 mg, 65%) as a white solid. The racemic material was separated by chiral SFC to give:

1-[(2,6-difluorophenyl)methyl]-N-(3R)-1,9-dimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 3.397 min) (26 mg, 37%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.65 (s, 1H), 8.33 (s, 1H), 7.50-7.44 (m, 1H), 7.09-7.02 (m, 2H), 5.62 (s, 2H), 4.65-4.60 (m, 1H), 4.50-4.46 (m, 1H), 4.13-4.08 (m, 1H), 3.32 (s, 3H), 2.73-2.65 (m, 1H), 2.32 (s, 3H), 2.26-2.15 (m, 1H). LCMS R_(T)=0.549 min; m/z=416.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.549 min, ESI+ found [M+H]=416.0

SFC conditions: Column: Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.8 mL/min Column temp.: 40° C.

Example 582

1-[(2-chlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 073 (RIP1K_experimental_3^(rd)_WX.doc). The crude was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonia hydroxide in water) to give 1-[(2-chlorophenyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (42.7 mg, 48%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.52 (s, 1H), 7.46 (d, J=6.8 Hz, 1H), 7.37-7.32 (m, 3H), 6.30 (s, 1H), 5.61 (s, 2H), 4.50-4.41 (m, 2H), 4.30-4.27 (m, 1H), 3.35 (s, 3H), 2.88-2.82 (m, 1H), 2.29-2.23 (m, 1H). LC-MS R_(T)=0.633 min, m/z=400.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.633 min, ESI+ found [M+H]=400.0.

Example 583 WX Method 052

N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-[[2-(trifluoromethyl)phenyl]methyl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (50 mg, 0.39 mmol) in N,N-dimethylformamide (3 mL) was added 2-(trifluoromethyl)benzyl bromide (112 mg, 0.47 mmol) and potassium carbonate (81 mg, 0.59 mmol). The mixture was stirred at 40° C. for 2 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.3) to afford methyl 1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxylate (100 mg, 89%) as colorless oil. LCMS R_(T)=0.690 min, m/z=286.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.690 min, ESI+ found [M+H=286.0

Step 2: 1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxylate (100 mg, 0.35 mmol) and lithium hydroxide (42 mg, 1.75 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 15° C. for 2 h. The mixture was filtered and the filtrate was adjusted to pH=6 by addition of 1N HCl. The solution was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxylic acid (86 mg, 90%) as a colorless oil, used as is in the next step.

Step 3: N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-[[2-(trifluoromethyl)phenyl]methyl-1,2,4-triazole-3-carboxamide

To a stirred solution of (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (25 mg, 0.14 mmol) in N,N-dimethylformamide (6 mL) was added 1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxylic acid (45 mg, 0.17 mmol), 1-hydroxybenzotriazole (28 mg, 0.21 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (40 mg, 0.21 mmol). The mixture was stirred at 20° C. for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to give N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxamide (17 mg, 28%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.55 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.66-7.60 (m, 1H), 7.57-7.49 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 6.30 (d, J=2.0 Hz, 1H), 5.70 (s, 2H), 4.51-4.49 (m, 1H), 4.45-4.37 (m, 1H), 4.32-4.21 (m, 1H), 3.34 (s, 3H), 2.89-2.83 (m, 1H), 2.32-2.26 (m, 1H).

LCMS R_(T)=0.935 min, m/z=434.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.935 min, ESI+ found [M+H]=434.3

Example 584

N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-[[2-(trifluoromethyl)phenyl]methyl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 052. The crude was purification by RP-HPLC (acetonitrile 17-47%/0.05 ammonium hydroxide in water) to give N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1-[[2-(trifluoro methyl)phenyl]methyl]-1,2,4-triazole-3-carboxamide (32 mg, 55%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.56 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.66-7.61 (m, 1H), 7.58-7.52 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.11 (s, 1H), 5.71 (s, 2H), 4.56-4.51 (m, 1H), 4.35-4.27 (m, 1H), 4.26-4.15 (m, 1H), 3.32 (s, 3H), 2.87-2.80 (m, 1H), 2.30-2.21 (m, 4H). LCMS R_(T)=0.971 min, m/z=448.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.971 min, ESI+ found [M+H]=448.3

Example 585 WX Method 055

1-benzyl-N-(6S)-2-cyclopropyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-benzyl-N-(6R)-2-cyclopropyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: 5-cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-1H-pyrazol-3-amine

To a solution of 2,4-dimethoxybenzaldehyde (29.7 g, 178.6 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (20.0 g, 162.4 mmol) in 1,2-dichloroethane (400 mL) was added acetic acid (9.75 g, 162.4 mmol). The reaction solution was stirred at 25° C. for 12 h, then sodium triacetoxyborohydride (51.6 g, 243.6 mmol) was added to the mixture. Stirring was continued for another 24 h and the reaction was quenched by addition of water (300 mL). The resulting mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford 5-cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-1H-pyrazol-3-amine (8.0 g, 18%) as yellow oil, used as is in the next step.

Step 2: 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-[(2,4-dimethoxyphenyl)methyl]butanamide

To a mixture of 5-cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-1H-pyrazol-3-amine (8.00 g, 29.3 mmol) and 4-dimethylaminopyridine (0.18 g, 1.5 mmol) in dichloromethane (400 mL) was added N,N-diisopropylethylamine (29.02 mL, 176.0 mmol) and 4-chlorobutanoyl chloride (19.65 mL, 176.0 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 12 h and then quenched by addition of methanol (5 mL). The mixture was stirred for 0.5 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-[(2,4-dimethoxyphenyl)methyl]butanamide (4.00 g, 36.2% yield) as yellow oil. LCMS R_(T)=1.07 min, m/z=378.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 1.07 min, ESI+ found [M+H]=378.2

Step 3: 2-cyclopropyl-4-[(3,5-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

A mixture of 4-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-[(2,4-dimethoxyphenyl)methyl]butanamide (4.0 g, 10.59 mmol) and potassium carbonate (4.4 g, 31.76 mmol) in N,N-dimethylformamide (80 mL) was stirred at 70° C. for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate in petroleum ether) to afford 2-cyclopropyl-4-[(3,5-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (2.0 g, 55.3% yield) as yellow oil.

LCMS R_(T)=0.816 min, m/z=342.3[M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.816 min, ESI+ found [M+H]=342.3

Step 4: 2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-6-iodo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (2.0 gg, 5.86 mmol) in dichloromethane (200 mL) was treated with N1,N1,N2,N2-tetramethylethane-1,2-diamine (6.8 g, 58.58 mmol) at −15° C., followed by iodotrimethylsilane (11.7 g, 58.58 mmol). Stirring at −15° C. was continued for 1.5 h, and then iodine (4.46 g, 17.57 mmol) was added. The mixture was stirred for another 3 h and then quenched by addition of saturated sodium sulphite (3 mL) and water (15 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford 2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-6-iodo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.0 g, 36.5% yield) as a light yellow solid. LCMS R_(T)=0.865 min, m/z=468.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.865 min, ESI+ found [M+H]=468.0

Step 5: 6-azido-2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-6-iodo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.0 g, 2.14 mmol) in N,N-dimethylformamide (20 mL) was added sodium azide (0.3 g, 4.28 mmol). The reaction mixture was stirred at 25° C. for 12 h and diluted with water (15 mL). The solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford 6-azido-2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (600 mg, 73%) as colorless oil. LCMS R_(T)=0.0.853 min, m/z=383.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.853 min, ESI+ found [M+H]=383.1

Step 6: 6-amino-2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 80% polymer-bound triphenylphosphine (5.1 g) in tetrahydrofuran (25 mL) was added water (5 mL) followed by 6-azido-2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (600 mg, 1.57 mmol). The mixture was stirred at 20° C. for 16 h. The mixture was filtered through Celite and concentrated to dryness. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% methanol in dichloromethane) to afford 6-amino-2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-5-one (400 mg, 72%) as yellow oil, used as is in the next step.

Step 7: 1-benzyl-N-[2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (200.0 mg, 0.56 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (136.8 mg, 0.67 mmol), 1-hydroxybenzotriazole (91.0 mg, 0.67 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (129.1 mg, 0.67 mmol). in N,N-dimethylformamide (6 mL) was stirred for 2 h at 20° C. This reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: 100-200 mesh, eluting 5% methanol in dichloromethane) to give 1-benzyl-N-[2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-5-oxo-7,8-dihydro-6H-pyrazol o[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (150 mg, 49.4% yield) as colorless oil. LCMS R_(T)=1.098 min, m/z=542.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 1.098 min, ESI+ found [M+H]=542.3

Step 8: 1-benzyl-N-(6S)-2-cyclopropyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide and 1-benzyl-N-(6R)-2-cyclopropyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-N-[2-cyclopropyl-4-[(2,4-dimethoxyphenyl)methyl]-5-oxo-7,8-dihydro-6H-pyrazol o[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (150.0 mg, 0.28 mmol) in trifluoroacetic acid (3.0 mL, 40 mmol) was stirred at 60° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17-47%/0.05% HCl in water) to afford 1-benzyl-N-(6S)-2-cyclopropyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1, 2,4-triazole-3-carboxamide (80 mg, 73.8% yield) as a white solid. The racemic material was separated by chiral SFC to give:

1-benzyl-N-[(6S)-2-cyclopropyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 3.786 min) (39.2 mg, 48.5% yield) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.82 (s, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.41-7.26 (m, 5H), 5.66 (s, 1H), 5.48 (s, 2H), 4.38-4.35 (m, 1H), 4.28-4.20 (m, 1H), 4.13-4.02 (m, 1H), 2.59-2.54 (m, 1H), 2.34-2.25 (m, 1H), 1.84-1.75 (m, 1H), 0.85-0.79 (m, 2H), 0.65-0.59 (m, 2H). LCMS R_(T)=0.869 min, m/z=392.0 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.869 min, ESI+ found [M+H]=392.0

1-benzyl-N-[(6R)-2-cyclopropyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.390 min) (40.0 mg, 50% yield) as white solids. ¹H NMR (400 MHz, DMSO-d6) δ10.32 (s, 1H), 8.82 (s, 1H), 8.48 (d, J=7.9 Hz, 1H), 7.41-7.26 (m, 5H), 5.66 (s, 1H), 5.48 (s, 2H), 4.37 (m, 1H), 4.28-4.20 (m, 1H), 4.13-4.02 (m, 1H), 2.59-2.54 (m, 1H), 2.34-2.25 (m, 1H), 1.84-1.75 (m, 1H), 0.85-0.79 (m, 2H), 0.65-0.59 (m, 2H). LCMS R_(T)=0.737 min, m/z=392.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.737 min, ESI+ found [M+H]=392.0

SFC condition: Column: Chiralpak AS-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:methanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 586 WX Method 054

1-benzyl-N-(6S)-2-methyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2, 4-triazole-3-carboxamide and 1-benzyl-N-(6R)-2-methyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2, 4-triazole-3-carboxamide

Step 1: N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazol-3-amine

To a solution of 2,4-dimethoxybenzaldehyde (18.8 g, 113.2 mmol) and 5-methyl-1H-pyrazol-3-amine (10.0 g, 102.9 mmol) in 1,2-dichloroethane (100 mL) was added acetic acid (6.1 g, 102.9 mmol). The reaction solution was stirred at 25° C. for 12 h, then sodium triacetoxyborohydride (32.7 g, 154.4 mmol) was added to the mixture. Stirring was continued for another 24 h and the reaction was quenched by addition of water (200 mL). The resulting mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 40 to 100% ethyl acetate in petroleum ether) to give N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazol-3-amine (3.0 g, 12%) as a brown oil, used as is in the next step. LCMS R_(T)=0.617 min, m/z=248.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.617 min, ESI+ found [M+H]=248.1

Step 2: 4-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(5-methyl-1H-pyrazol-3-yl)butanamide

To a solution of N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-1H-pyrazol-3-amine (7.00 g, 28.31 mmol) and N,N-diisopropylethylamine (17.42 mL, 169.84 mmol) in dichloromethane (150 mL) was added 4-dimethylaminopyridine (0.35 g, 2.83 mmol) and 4-chlorobutanoyl chloride (11.97 g, 84.92 mmol) at 0° C. After addition, the mixture was stirred at 20° C. for 12 h and then quenched by addition of methanol (10 mL). The mixture was stirred for 0.5 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 4-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(5-methyl-1H-pyrazol-3-yl)butanamide (2.5 g, 25.1% yield) as slight yellow oil. LCMS R_(T)=0.875 min, m/z=352.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.875 min, ESI+ found [M+H]=352.1

Step 3: 4-[(3,5-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

A mixture of 4-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(5-methyl-1H-pyrazol-3-yl)butanamide (800 mg, 2.27 mmol) and cesium carbonate (1482 mg, 4.55 mmol) in N,N-dimethylformamide (10 mL) was stirred at 20° C. for 3 h and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 4-[(3,5-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (400 mg, 55.8%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ7.00 (d, J=8 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.48-6.41 (m, 1H), 5.77 (s, 1H), 4.69 (s, 2H), 4.01-3.98 (m, 2H), 3.69 (d, J=8.8 Hz, 6H), 2.26-2.14 (m, 4H), 2.04 (s, 3H).

Step 4: 4-[(2,4-dimethoxyphenyl)methyl]-6-iodo-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.16 mmol) in dichloromethane (20 mL) was treated with N1,N1,N2,N2-tetramethylethane-1,2-diamine (184 mg, 1.59 mmol) at −15° C., followed by iodotrimethylsilane (317 mg, 1.59 mmol). Stirring at −15° C. was continued for 1.5 h, and then iodine (120 mg, 0.48 mmol) was added. The mixture was stirred for another 3 h and then quenched by addition of saturated sodium sulphite (3 mL) and water (15 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.5) to afford 4-[(2,4-dimethoxyphenyl)methyl]-6-iodo-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 72%) as a yellow solid, used as is in the next step.

Step 5: 6-azido-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

To a solution of 4-[(2,4-dimethoxyphenyl)methyl]-6-iodo-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (40 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL) was added sodium azide (147 mg, 2.27 mmol). The reaction mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether, R_(f)=0.5) to afford 6-azido-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (25 mg, 77%) as a white solid, used as is in the next step.

Step 6: 6-amino-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

A mixture of 6-azido-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.08 mmol) and palladium (10% on carbon, 22 mg, 0.02 mmol) in methanol (15 mL) was hydrogenated (15 psi) at 25° C. for 2 h and then filtered. The filtrate was concentrated under reduced pressure to afford 6-amino-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (25 mg, 90%) as a colorless oil. LCMS R_(T)=0.618 min, m/z=331.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.618 min, ESI+ found [M+H]=331.0

Step 7: 1-benzyl-N-[4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.06 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (16 mg, 0.08 mmol), 1-hydroxybenzotriazole (12 mg, 0.09 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (17 mg, 0.09 mmol). in N,N-dimethylformamide (3 mL) was stirred for 40 min at 40° C. This reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (10% methanol in dichloromethane, R_(f)=0.3) to afford 1-benzyl-N-[4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (20 mg, 64%) as a white solid. LCMS R_(T)=1.068 min, m/z=515.9 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 1.068 min, ESI+ found [M+H]=515.9

Step 8: 1-benzyl-N-(6S)-2-methyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2, 4-triazole-3-carboxamide and 1-benzyl-N-(6R)-2-methyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2, 4-triazole-3-carboxamide

A mixture of 1-benzyl-N-[4-[(2,4-dimethoxyphenyl)methyl]-2-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (60.0 mg, 0.12 mmol) in trifluoroacetic acid (1.5 mL, 20 mmol) was stirred at 60° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 18-48%/0.05% FA in water) to afford 1-benzyl-N-(2-methyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide (40 mg, 94.1% yield) as a white solid. The racemic material was separated by chiral SFC to give:

1-benzyl-N-(6S)-2-methyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.974 min) (7 mg, 17%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.45 (d, J=7.6 Hz, 1H), 7.38-7.25 (m, 5H), 5.72 (s, 1H), 5.46 (s, 2H), 4.39-4.34 (m, 1H), 4.28-4.19 (m, 1H), 4.13-4.01 (m, 1H), 2.64 (s, 1H), 2.30 (s, 1H), 2.09 (s, 3H). LCMS R_(T)=0.689 min, m/z=366.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.689 min, ESI+ found [M+H]=366.0

1-benzyl-N-(6R)-2-methyl-5-oxo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.659 min) (8.9 mg, 22%) as white solids. ¹H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 7.38-7.25 (m, 5H), 5.72 (s, 1H), 5.46 (s, 2H), 4.36 (m, 1H), 4.28-4.19 (m, 1H), 4.13-4.01 (m, 1H), 2.64 (s, 1H), 2.30 (s, 1H), 2.09 (s, 3H). LCMS R_(T)=0.684 min, m/z=366.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.684 min, ESI+ found [M+H]=366.1

SFC conditions: Column: Chiralpak AS-H 250×4.6 mm I.D., 5 umMobile phase: A: CO2 B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 5.0 min and hold 40% for 2.5 min, then 5% of B for 2.5 minFlow rate: 2.5 mL/min Column temperature: 35° C.

Example 587 WX Method 034

1-[(2-methoxyphenyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: 1-(bromomethyl)-2-methoxybenzene

A mixture of 2-methylanisole (2.0 g, 16.37 mmol), NBS (2.91 g, 16.37 mmol) and AIBN (0.05 g, 0.28 mmol) in 1,2-dichloroethane (30 mL) was stirred for 3 h at 88° C. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to afford 1-(bromomethyl)-2-methoxy-benzene (1.2 g, 37%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.25 (m, 2H), 6.94-6.87 (m, 2H), 4.57 (s, 2H), 3.90 (s, 3H).

Step 2: methyl 1-(2-methoxybenzyl)-1H-1,2,4-triazole-3-carboxylate

A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (395 mg, 3.11 mmol), potassium carbonate (859 mg, 6.22 mmol) and 1-(bromomethyl)-2-methoxybenzene (750 mg, 3.73 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford methyl 1-[(2-methoxyphenyl)methyl]-1,2,4-triazole-3-carboxylate (400 mg, 52%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.38-7.29 (m, 2H), 6.98-6.90 (m, 2H), 5.40 (s, 2H), 3.97 (s, 3H), 3.84 (s, 3H).

Step 3: 1-(2-methoxybenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(2-methoxyphenyl)methyl]-1,2,4-triazole-3-carboxylate (230 mg, 0.93 mmol) and lithium hydroxide (111 mg, 4.65 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was stirred for 3 h at 25° C. and the organic solvent was evaporated under reduced pressure. The aqueous residue was adjusted to pH=1-2 by addition of 20% aqueous HCl. The resulting solid was collected by filtration and dried to give crude 1-[(2-methoxyphenyl)methyl]-1,2,4-triazole-3-carboxylic acid (150 mg, 69%) as a white solid, used as is in the next step.

Step 4: 1-[(2-methoxyphenyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a stirred solution of 1-[(2-methoxyphenyl)methyl]-1,2,4-triazole-3-carboxylic acid (49 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was added (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (32 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (51 mg, 0.27 mmol) and 1-hydroxybenzotriazole (36 mg, 0.27 mmol). The mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to afford 1-[(2-methoxyphenyl)methyl]-N-(6 S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (36 mg, 50%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 7.51 (s, 1H), 7.36-7.32 (m, 1H), 7.28-7.26 (m, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.96-6.93 (m, 1H), 6.29 (s, 1H), 5.42 (s, 2H), 4.51-4.46 (m, 1H), 4.44-4.38 (m, 1H), 4.30-4.22 (m, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 2.89-2.79 (m, 1H), 2.29-2.21 (m, 1H). LCMS R_(T)=1.48 min, m/z=396.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.48 min, ESI+ found [M+H]=396.1.

Example 588 WX Method 062

1-(o-tolylmethyl)-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (200 mg, 1.57 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (435 mg, 3.14 mmol) and 1-(bromomethyl)-2-methylbenzene (349 mg, 1.89 mmol). The mixture was stirred at 25° C. for 2 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 80% ethyl acetate in petroleum ether) to afford methyl 1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxylate (240 mg, 66%) as a white solid, used as is in the next step.

Step 2: 1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxylate (240 mg, 1.03 mmol) and potassium hydroxide (124 mg, 5.19 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25° C. for 2 h. The organic solvents were evaporated under reduced pressure and the mixture was diluted with water (20 mL). The solution was adjusted to pH=4 by addition of 2N HCl. The resulting solid was collected by filtration and dried to give crude 1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxylic acid (180 mg, 80%) as a white solid, use as is in the next step.

Step 3: 1-(o-tolylmethyl)-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (40 mg, 0.22 mmol), 1-(o-tolylmethyl)-1,2,4-triazole-3-carboxylic acid (51 mg, 0.23 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (64 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20° C. for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to afford 1-(o-tolylmethyl)-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo][1,3-4]-methyl-5-oxo-71,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (44 mg, 51%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 7.52-7.51 (m, 1H), 7.26-7.15 (m, 4H), 6.31-6.30 (m, 1H), 5.50 (s, 2H), 4.53-4.40 (m, 2H), 4.30-4.25 (m, 1H), 3.35 (s, 3H), 2.89-2.83 (m, 1H), 2.34 (s, 3H), 2.31-2.23 (m, 1H). LCMS R_(T)=1.48 min; m/z=380.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide acid over 3 mins) retention time 1.48 min, ESI+ found [M+H]=380.2.

Example 589

1-[(2-methoxyphenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 034. The crude was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to give 1-[(2-methoxyphenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (47 mg, 60%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 7.36-7.32 (m, 1H), 7.30-7.26 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.96-6.92 (m, 1H), 6.09 (s, 1H), 5.42 (s, 2H), 4.53-4.48 (m, 1H), 4.32-4.26 (m, 1H), 4.23-4.15 (m, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 2.87-2.76 (m, 1H), 2.24 (s, 3H), 2.26-2.18 (m, 1H).

LCMS R_(T)=1.55 min, m/z=410.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.55 min, ESI+ found [M+H]=410.1.

Example 590

1-[(2-cyanophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 059. The crude was purified by RP-HPLC (acetonitrile 20-50%/HCl in water) to give 1-[(2-cyanophenyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (26 mg, 36%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.79 (s, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.74-7.68 (m, 1H), 7.59-7.53 (m, 1H), 7.51-7.49 (m, 1H), 6.44 (s, 1H), 5.74 (s, 2H), 4.73-4.68 (m, 1H), 4.51-4.44 (m, 1H), 4.42-4.33 (m, 1H), 3.37 (s, 3H), 2.94-2.82 (m, 1H), 2.46-2.35 (m, 4H). LCMS R_(T)=1.544 min; m/z=405.3 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.544 min, ESI+ found [M+H]=405.3.

Example 591

1-(o-tolylmethyl)-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 062. The crude was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give 1-(o-tolylmethyl)-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (20 mg, 25%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.45 (s, 1H), 7.26-7.22 (m, 2H), 7.20-7.15 (m, 2H), 6.11 (s, 1H), 5.50 (s, 2H), 4.55-4.50 (m, 1H), 4.30-4.28 (m, 1H), 4.23-4.20 (m, 1H), 3.32 (s, 3H), 2.87-2.81 (m, 1H), 2.34 (s, 3H), 2.28-2.20 (m, 4H). LCMS R_(T)=1.565 min; m/z=394.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide acid over 3 mins) retention time 1.565 min, ESI+ found [M+H]=394.2.

Example 592

1-[(2-methoxyphenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 034. The crude was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to give 1-[(2-methoxyphenyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol o[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (42 mg, 53%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 7.36-7.32 (m, 1H), 7.30-7.26 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.96-6.92 (m, 1H), 5.98 (s, 1H), 5.42 (s, 2H), 4.53-4.48 (m, 1H), 4.32-4.26 (m, 1H), 4.23-4.15 (m, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 2.83-2.78 (m, 1H), 2.22-2.20 (m, 1H), 1.91-1.86 (m, 1H), 0.93-0.91 (m, 2H), 0.73-0.71 (m, 2H). LCMS R_(T)=1.68 min, m/z=436.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.68 min, ESI+ found [M+H]=436.1.

Example 593 WX Method 059

1-[(2-cyanophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(2-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of 2-(bromomethyl)benzonitrile (386 mg, 1.97 mmol) in N,N-dimethylformamide (3 mL) was added methyl 1H-1,2,4-triazole-3-carboxylate (250 mg, 1.97 mmol) and potassium carbonate (408 mg, 2.95 mmol). The mixture was stirred at 25° C. for 2 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% petroleum ether) to give methyl 1-[(2-cyanophenyl)methyl]-1,2,4-triazole-3-carboxylate (240 mg, 50%) as a white solid, used as is in the next step.

Step 2: 1-(2-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(2-cyanophenyl)methyl]-1,2,4-triazole-3-carboxylate (150 mg, 0.62 mmol) and lithium hydroxide (74 mg, 3.1 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at for 2 h. The organic solvent was evaporated under reduced pressure and the aqueous solution was adjusted to pH=5 by addition of 1N HCl. The resulting mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were concentrated under reduced pressure to afford crude methyl 1-[(2-cyanophenyl)methyl]-1,2,4-triazole-3-carboxylate (150 mg, 85%) as a white solid, used as is in the next step.

Step 3: 1-[(2-cyanophenyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of (6S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (38 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and 1-[(2-cyanophenyl)methyl]-1,2,4-triazole-3-carboxylic acid (40 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 22-52%/HCl in water) to afford 1-[(2-cyanophenyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (46 mg, 61%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.84 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.73-7.68 (m, 1H), 7.59-7.48 (m, 2H), 6.38 (s, 1H), 5.75 (s, 2H), 4.75-4.70 (m, 1H), 4.54-4.45 (m, 1H), 4.42-4.33 (m, 1H), 3.36 (s, 3H), 2.94-2.83 (m, 1H), 2.46-2.36 (m, 1H), 2.09-2.01 (m, 1H), 1.20-1.17 (m, 2H), 1.00-0.91 (m, 2H). LCMS R_(T)=1.65 min; m/z=431.3 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 1.65 min, ESI+ found [M+H]=431.3.

Example 594

1-[(3,3-difluorocyclopentyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

N-Alkylation prepared in a similar fashion to WX Method 041. The crude was purified by RP-HPLC (acetonitrile 0-40%/0.05% ammonium hydroxide in water) to give 1-[(3,3-difluorocyclopentyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (9.1 mg, 32%). ¹H NMR (400 MHz, CD₃OD) δ8.51 (s, 1H), 6.01 (s, 1H), 4.57-4.50 (m, 1H), 4.35-4.27 (m, 3H), 4.24-4.16 (m, 1H), 3.32 (s, 3H), 2.92-2.70 (m, 3H), 2.29-2.11 (m, 3H), 1.97-1.83 (m, 3H), 1.63-1.55 (m, 1H), 0.99-0.91 (m, 2H), 0.79-0.69 (m, 2H). LC-MS R_(T)=0.945 min, m/z=434.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% TFA over 2.0 mins) retention time 0.945 min, ESI+ found [M+H]=434.3

Example 595

1-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 140. The crude was purified by RP-HPLC (35% to 65% acetonitrile/0.05% HCl in water) to afford 1-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (19 mg, 27%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 9.53 (s, 1H), 9.23 (d, J=7.2 Hz, 1H), 8.70 (s, 1H), 7.74-7.67 (m, 1H), 7.46-7.40 (m, 1H), 7.34-7.28 (m, 3H), 7.26-7.21 (m, 1H), 5.06-5.01 (m, 1H), 4.69-4.65 (m, 1H), 4.45-4.38 (m, 1H), 3.42 (s, 3H). LCMS R_(T)=1.851 min; m/z=451.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.851 min, ESI+ found [M+H]=451.2.

Example 596

1-[(2-fluorophenyl)methyl]-N-(3R)-1,7,9-trimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 096. The crude was purified by RP-HPLC (18% to 48% acetonitrile/0.05% ammonia hydroxide in water) to give 1-(2-fluorobenzyl)-N-(1,7,9-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (70 mg, 71%) as a white solid. The racemic compound was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-(3R)-1,7,9-trimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.147 min) (18.9 mg, 31.2%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.58 (s, 1H), 7.43-7.36 (m, 2H), 7.22-7.12 (m, 2H), 5.48 (s, 2H), 4.57-4.52 (m, 1H), 4.25-4.19 (m, 1H), 3.83-3.79 (m, 1H), 3.30 (s, 3H), 2.68-2.62 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 2.09-2.05 (m, 1H). LCMS R_(T)=0.724 min, m/z=412.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.724 min, ESI+ found [M+H]=412.0

SFC conditions: Column: Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.8 mL/min Column temp.: 40° C.

Example 597

1-[(2,6-difluorophenyl)methyl]-N-(3R)-1,7,9-trimethyl-2-oxo-4,5-dihydro-3H-imidazo[1, 5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 096. The crude was purified by RP-HPLC (18% to 48% acetonitrile/0.05% ammonia hydroxide in water) to give 1-(2,6-difluorobenzyl)-N-(1,7,9-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]di azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (70 mg, 71%) as a white solid. The racemic material was separated by chiral SFC to give:

1-[(2,6-difluorophenyl)methyl]-N-(3R)-1,7,9-trimethyl-2-oxo-4, 5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 3.054 min) (25.1 mg, 41.4%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.61 (s, 1H), 7.50-7.42 (m, 1H), 7.08-7.03 (m, 2H), 5.48 (s, 2H), 4.57-4.52 (m, 1H), 4.25-4.19 (m, 1H), 3.83-3.79 (m, 1H), 3.30 (s, 3H), 2.68-2.62 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 2.09-2.05 (m, 1H). LCMS R_(T)=0.544 min; m/z=430.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.544 min, ESI+ found [M+H]=430.1

SFC condition Column: Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.8 mL/min Column temp.: 40° C.

Example 598

1-[(2,5-difluorophenyl)methyl]-N-(3R)-1,7,9-trimethyl-2-oxo-4,5-dihydro-3H-imidazo[1, 5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 096. The crude was purified by RP-HPLC (18% to 48% acetonitrile/0.05% ammonia hydroxide in water) to give 1-(2,5-difluorobenzyl)-N-(1,7,9-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]di azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (70 mg, 71%) as a white solid. The racemic material was separated by chiral SFC to give:

1-[(2,5-difluorophenyl)methyl]-N-(3R)-1,7,9-trimethyl-2-oxo-4, 5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 3.240 min) (21.7 mg, 36%). ¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 7.19-7.13 (m, 3H), 5.54 (s, 2H), 4.57-4.52 (m, 1H), 4.25-4.19 (m, 1H), 3.83-3.79 (m, 1H), 3.30 (s, 3H), 2.68-2.62 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 2.09-2.05 (m, 1H). LCMS R_(T)=0.540 min; m/z=430.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.540 min, ESI+ found [M+H]=430.0

SFC condition: Column: Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.8 mL/min Column temp.: 40° C.

Example 599

1-[(2-fluorophenyl)methyl]-N-(3R)-1-methyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 043. The obtained racemic compound was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-(3R)-1-methyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time=3.432 min) (17.3 mg, 34%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.47 (d, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.44-7.33 (m, 2H), 7.27-7.19 (m, 2H), 6.95 (s, 1H), 5.55 (s, 2H), 4.38-4.31 (m, 2H), 3.88-3.81 (m, 1H), 3.23 (s, 3H), 2.44 (s, 1H), 2.27-2.21 (m, 1H). LCMS R_(T)=1.693 min, m/z=384.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.693 min, ESI+ found [M+H]=384.2.

SFC conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:methanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 600

1-[(2,6-difluorophenyl)methyl]-N-[(3R)-1-methyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 096. The obtained racemic compound was separated by chiral SFC to give:

1-[(2,6-difluorophenyl)methyl]-N-[(3R)-1-methyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.941 min) (49.1 mg 49%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.61-7.43 (m, 2H), 7.20-7.16 (m, 2H), 6.95 (s, 1H), 5.56 (s, 2H), 4.39-4.25 (m, 2H), 3.88-3.78 (m, 1H), 3.22 (s, 3H), 2.48-2.39 (m, 1H), 2.27-2.20 (m, 1H). LCMS R_(T)=1.681 min; m/z=402.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.681 min, ESI+ found [M+H]=402.1

SFC condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:Methanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 601

1-[(2-fluorophenyl)methyl]-N-(7R)-9-methyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 043. The obtained racemic compound was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-(7R)-9-methyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.621 min) (19 mg, 47.5%): ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.42-7.34 (m, 2H), 7.21-7.11 (m, 2H), 7.08 (s, 1H), 6.95 (s, 1H), 5.54 (s, 2H), 4.54-4.47 (m, 1H), 4.32-4.25 (m, 1H), 4.09-4.02 (m, 1H), 3.38 (s, 3H), 2.87-2.79 (m, 1H), 2.28-2.23 (m, 1H). LCMS R_(T)=1.293 min, m/z=384.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.293, ESI+ found [M+H]=384.2.

SFC conditions: Column: Chiralcel OJ-3 250×30 mm I.D., 10 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 25% to 25%, Flow rate: 60 mL/min, Column temp.: 40° C.

Example 602

1-[(2,6-difluorophenyl)methyl]-N-[(7R)-9-methyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 096. The obtained racemic compound was separated by chiral SFC to give:

1-[(2,6-difluorophenyl)methyl]-N-[(7R)-9-methyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.289 min) (19 mg, 47.5%) as white solids. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.53 (d, J=7.6 Hz, 1H), 7.55-7.46 (m, 1H), 7.17 (t, J=8.0 Hz, 2H), 7.12 (s, 1H), 6.87 (s, 1H), 5.56 (s, 2H), 4.29-4.23 (m, 2H), 3.95-3.87 (m, 1H), 3.24 (s, 3H), 3.51-3.50 (m, 1H), 2.38-2.34 (m, 1H). LCMS R_(T)=1.293 min; m/z=402.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.293, ESI+ found [M+H]=402.1

SFC condition: Column: Chiralcel OJ-3 250×30 mm I.D., 10 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 25% to 25%, Flow rate: 60 mL/min, Column temp.: 40° C.

Example 603

1-[(2-cyanophenyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 059. The crude was purified by RP-HPLC (acetonitrile 14-44%/HCl in water) to give 1-[(2-cyanophenyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-c arboxamide (12 mg, 17%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.80 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.74-7.68 (m, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.58-7.53 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 5.74 (s, 2H), 4.57-4.52 (m, 1H), 4.50-4.44 (m, 1H), 4.38-4.27 (m, 1H), 3.36 (s, 3H), 2.91-2.81 (m, 1H), 2.35-2.28 (m, 1H). LCMS R_(T)=1.732 min; m/z=391.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium hydroxide acid over 3 mins) retention time 1.732 min, ESI+ found [M+H]=391.1.

Example 604

1-(o-tolylmethyl)-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 062. The crude was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide in water) to give 1-(o-tolylmethyl)-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (38 mg, 49%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 7.26-7.15 (m, 4H), 6.00 (s, 1H), 5.50 (s, 2H), 4.45-4.49 (m, 1H), 4.28-4.23 (m, 1H), 4.20-4.18 (m, 1H), 3.35 (s, 3H), 2.85-2.80 (m, 1H), 2.34 (s, 3H), 2.24-2.22 (m, 1H), 1.92-1.88 (m, 1H), 0.95-0.92 (m, 2H), 0.75-0.72 (m, 2H). LCMS R_(T)=1.69 min; m/z=420.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium hydroxide acid over 3 mins) retention time 1.69 min, ESI+ found [M+H]=420.2.

Example 605

1-isopropyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 142. The crude was purified by RP-HPLC (acetonitrile 32% to 62%/0.05% ammonium hydroxide in water) to give 1-isopropyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (14.7 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ9.36 (s, 1H), 8.39 (s, 1H), 6.98-6.88 (m, 2H), 5.46-5.42 (m, 1H), 5.16-5.13 (m, 1H), 4.80-4.76 (m, 1H), 4.58 (t, J=10.4 Hz, 1H), 1.60 (d, J=6.4 Hz, 6H). LCMS R_(T)=0.787 min, m/z=403.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.787 min, ESI+ found [M+H]=403.0.

Example 606

1-isopropyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 142. The crude was purified by RP-HPLC (acetonitrile 32% to 62%/0.05% ammonium hydroxide in water) to give 1-isopropyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (19.4 mg, 33%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ9.36 (s, 1H), 8.39 (s, 1H), 6.91-6.88 (m, 2H), 5.47-5.42 (m, 1H), 5.12-5.09 (m, 1H), 4.76-4.72 (m, 1H), 4.51 (t, J=10.4 Hz, 1H), 2.36 (s, 3H), 1.60 (d, J=6.4 Hz, 6H).

LCMS R_(T)=0.787 min, m/z=399.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.787 min, ESI+ found [M+H]=399.0.

Example 607

1-isopropyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]pyrazolo[3, 4-d]pyrimidine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 142. The crude was purified by RP-HPLC (acetonitrile 35% to 65%/0.05% ammonium hydroxide in water) to give 1-isopropyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (34.7 mg, 60%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ9.35 (s, 1H), 8.38 (s, 1H), 7.05-7.00 (m, 2H), 5.45-5.40 (m, 1H), 4.69-4.64 (m, 1H), 3.05-3.02 (m, 1H), 2.89-2.76 (m, 2H), 2.32-2.26 (m, 1H), 1.60 (d, J=6.8 Hz, 6H). LCMS R_(T)=0.770 min, m/z=401.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.770 min, ESI+ found [M+H]=401.0.

Example 608 WX Method 096

1-benzyl-N-(3R)-1,7,9-trimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

Step 1: 7-bromo-1,9-dimethyl-4,5-dihydro-1H-imidazo[1,5-a][1,3]diazepin-2(3H)-one

To a solution of 1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (500 mg, 2.79 mmol) in chloroform (20 mL) was added 1-bromo-2,5-pyrrolidinedione (596 mg, 3.35 mmol). The reaction mixture was heated at 70° C. for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 7-bromo-1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (720 mg, 100%) as a yellow solid, used as is in the next step.

Step 2: 1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one

A mixture of 7-bromo-1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (600 mg, 2.32 mmol), trimethylboroxine (584 mg, 4.65 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (170 mg, 0.23 mmol) and cesium carbonate (1.51 g, 4.65 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 95° C. for 3 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (5% to 35% acetonitrile, 0.05% ammonia hydroxide in water) to afford 1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (220 mg, 49%) as a white solid, used as is in the next step.

Step 3: 3-iodo-1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one

To a solution of 1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (220 mg, 1.14 mmol) in dichloromethane (15 mL) was added N1,N1,N3,N3-tetramethylpropane-1,3-diamine (1.06 g, 9.11 mmol) and iodotrimethylsilane (1.82 g, 9.11 mmol) at −15° C. The reaction mixture was stirred at −15° C. for 2 h and iodine (867 mg, 3.42 mmol) was added. The mixture was stirred at −15° C. for another 2 h and quenched by addition of saturated aqueous sodium sulfite (20 mL). The resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 3-iodo-1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (350 mg, 96%) as a white solid, used as is in the next step.

Step 3: 3-azido-1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one

A mixture of 3-iodo-1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (350 mg, 1.15 mmol) and sodium azide (500 mg, 7.69 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 3 h and then diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude azido-1,9-dimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (250 mg, 99%) as colorless oil, used as is in the next step.

Step 4: 3-amino-1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one

A mixture of 3-azido-1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (250 mg, 1.07 mmol) and Pd/C (10%, 114 mg, 0.11 mmol) in methanol (30 mL) was hydrogenated (15 psi) for 2 h and filtered. The filtrate was concentrated under reduced pressure to afford crude 3-amino-1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (200 mg, 90%) as a white solid used as is in the next step.

Step 5: 1-benzyl-N-(3R)-1,7,9-trimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide

A mixture of 3-amino-1,7,9-trimethyl-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-2-one (30 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (27 mg, 0.14 mmol), 1-hydroxybenzotriazole (19 mg, 0.14 mmol) and 1-benzyl-1,2,4-triazole-3-carboxylic acid (29 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (18% to 48% acetonitrile/0.05% ammonia hydroxide in water) to afford 1-benzyl-N-(1,7,9-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 71%) as a white solid. The racemic compound was separated by chiral SFC to give:

1-benzyl-N-(3R)-1,7,9-trimethyl-2-oxo-4,5-dihydro-3H-imidazo[1,5-a][1,3]diazepin-3-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.482 min) (12.1 mg, 30%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ8.57 (s, 1H), 7.39-7.35 (m, 5H), 5.48 (s, 2H), 4.57-4.52 (m, 1H), 4.25-4.19 (m, 1H), 3.83-3.79 (m, 1H), 3.30 (s, 3H), 2.68-2.62 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 2.09-2.05 (m, 1H). LCMS R_(T)=1.332 min; m/z=394.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.332 min, ESI+ found [M+H]=394.2.

SFC conditions: Column: Chiralpak OJ-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.8 mL/min Column temp.: 40° C.

Example 609 WX Method 140

1-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: (Z)-2,4,6-trichloro-5-((2-(2,6-difluorophenyl)hydrazono)methyl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.0 g, 4.73 mmol) in tetrahydrofuran (400 mL) was added (2,6-difluorophenyl)hydrazine (682 mg, 4.73 mmol) at 0° C. The mixture was stirred at 20° C. for 1.5 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give (Z)-2,4,6-trichloro-5-((2-(2,6-difluorophenyl)hydrazono)methyl)pyrimidine (1.2 g, 75%) as a yellow solid, used as is in the next step.

Step 2: 4,6-dichloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine

A solution of 2,6-difluoro-N—[(Z)-(2,4,6-trichloropyrimidin-5-yl) methyleneamino]aniline (600 mg, 1.78 mmol) in acetonitrile (4 mL) was heated at 150° C. for 1.5 h under microwave conditions. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 4,6-dichloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine (500 mg, 93%) as a white solid, used as is in the next step.

Step 3: 6-chloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine

A mixture of 4,6-dichloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine (500 mg, 1.66 mmol), zinc (326 mg, 4.98 mmol) in water (10 mL) and tetrahydrofuran (10 mL) was heated at 100° C. for 1 h. After cooled, the reaction was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), brine (1×10 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to afford 6-chloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine (350 mg, 79%) as a white solid, used as is in the next step.

Step 4: 1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

To a solution of 1,4-diazabicyclo[2.2.2]octane (63 mg, 0.56 mmol) and sodium cyanide (110 mg, 2.25 mmol) in dimethyl sulfoxide (8 mL) was added 6-chloro-1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine (300 mg, 1.13 mmol) in water (4 mL). The reaction mixture was stirred at 25° C. for 12 h and extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-carbonitrile (100 mg, 35%) as a yellow solid, used as is in the next step.

Step 5: methyl 1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

To a solution of 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-carbonitrile (100 mg, 0.39 mmol) in methanol (5 mL) was added HCl (4 N in methanol, 5 mL). The reaction mixture was stirred at 20° C. for 3 h and concentrated under reduced pressure to afford crude methyl 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-carboxylate (50 mg, 44%) as a yellow oil, used as is in the next step.

Step 6: 1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

A mixture of methyl 1-(2,6-difluorophenyl)pyrazol o[3,4-d]pyrimidine-6-carboxylate (40 mg, 0.14 mmol) and lithium hydroxide (23 mg, 0.55 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at 20° C. for 2 h. The organic solvent was concentrated under reduced pressure and the aqueous solution was adjusted to pH=3 by addition of 1N HCl. The mixture was extracted with dichloromethane (2×10 mL). The combined organic layers were concentrated under reduced pressure to afford crude 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 78%) as a yellow solid, used as is in the next step.

Step 6: 1-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

A mixture of (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol), 1-(2,6-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (30 mg, 0.11 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (50 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (30% to 60% acetonitrile/0.05% HCl in water) to afford 1-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (25 mg, 48%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ9.58 (s, 1H), 8.76 (s, 1H), 7.77-7.68 (m, 1H), 7.35-7.31 (m, 2H), 6.35 (s, 1H), 4.73-4.71 (m, 1H), 4.47-4.40 (m, 1H), 4.38-4.31 (m, 1H), 3.38 (s, 3H), 3.00-2.92 (m, 1H), 2.42-2.30 (m, 4H). LCMS R_(T)=0.934 min; m/z=453.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.934 min, ESI+ found [M+H]=453.3.

Example 610 WX Method 103

(S)—N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: 1-amino-5-phenyl-pyrrolidin-2-one

To a solution of tert-butyl N-(2-oxo-5-phenyl-pyrrolidin-1-yl)carbamate (350 mg, 1.3 mmol) in ethyl acetate (3 mL) was added HCl (4N in ethyl acetate, 3.0 mL, 12.0 mmol). The mixture was stirred at 20° C. for 1 h and concentrated under reduced pressure. The residue was quenched by addition of saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (3×20 mL), brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 1-amino-5-phenyl-pyrrolidin-2-one (190 mg, 85%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.42-7.32 (m, 3H), 7.24 (d, J=7.6 Hz, 2H), 4.66-4.62 (m, 1H), 3.95 (br. s, 2H), 2.63-2.45 (m, 3H), 1.91-1.88 (m, 1H).

Step 2: ethyl (2Z)-2-amino-2-(2-oxo-5-phenyl-pyrrolidin-1-yl)imino-acetate

To a stirred solution of 1-amino-5-phenyl-pyrrolidin-2-one (270 mg, 1.53 mmol) in ethanol (8.0 mL) was added ethyl amino (thioxo)acetate (224 mg, 1.69 mmol). The mixture was stirred at 90° C. for 4 h and cooled to room temperature. The solution was diluted with ethyl acetate (15 mL), washed with water (2×5 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude ethyl (2Z)-2-amino-2-(2-oxo-5-phenyl-pyrrolidin-1-yl)imino-acetate (400 mg, 95%) as a yellow oil. LCMS R_(T)=0.581 min, m/z=275.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.581 min, ESI+ found [M+H]=275.9.

Step 3: (S)-ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate and (R)-ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A solution of ethyl (2Z)-2-amino-2-(2-oxo-5-phenyl-pyrrolidin-1-yl)imino-acetate (400 mg, 1.45 mmol) in POCl₃ (2 mL) was stirred at 120° C. for 1 h. After cooled, the mixture was quenched by addition of saturated sodium bicarbonate (15 mL). The resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-70% ethyl acetate in petroleum) to afford ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (310 mg, 81%) as a yellow oil. The racemic material was separated by chiral SFC to give:

(S)-ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (Peak 1, retention time=4.063 min) (130 mg, 42%) as a yellow oil. LCMS R_(T)=0.629 min, m/z=257.8 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.629 min, ESI+ found [M+H]=257.8.

(R)-ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (Peak 1, retention time=5.844 min) (135 mg, 43%) as a yellow oil. LCMS R_(T)=0.631 min, m/z=257.8 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.631 min, ESI+ found [M+H]=257.8.

SFC condition: column: Lux Cellulose-2 150×4.6 mm I.D., 3 μm mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 5 to 40 of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Step 4: (S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

To a solution of ethyl (5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (130 mg, 0.51 mmol) in tetrahydrofuran (2 mL)/methanol (2 mL)/water (1 mL) was added lithium hydroxide hydrate (127.2 mg, 3.03 mmol). The mixture was stirred at 25° C. for 1 h and diluted with water (10 mL). The solution was adjusted to pH=4-5 by addition of 1N HCl. The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude (S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (105 mg, 90%) as a light yellow solid, used as is in the next step.

Step 5: (S)—N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.15 mmol), (S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (35 mg, 0.15 mmol), N¹-((ethylimino)methyl ene)-N³,N³-di methylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (31 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (26% to 56% acetonitrile/0.05% ammonia hydroxide in water) to give (S)—N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (48.3 mg, 76%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.38-7.34 (m, 3H), 7.21-7.20 (m, 2H), 6.10 (s, 1H), 5.55-5.52 (m, 1H), 4.53-4.48 (m, 1H), 4.28-4.26 (m, 1H), 4.21-4.18 (m, 1H), 3.31 (s, 3H), 3.26-3.24 (m, 1H), 3.14-3.12 (m, 1H), 3.06-3.04 (m, 1H), 2.91-2.80 (m, 1H), 2.66-2.64 (m, 1H), 2.24-2.20 (m, 4H). LCMS R_(T)=0.752 min, m/z=406.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.752 min, ESI+ found [M+H]=406.1.

Example 611

(5S)-5-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 103. The crude was purified by RP-HPLC (35% to 65% acetonitrile/0.05% ammonia hydroxide in water) to afford (5S)-5-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (21.9 mg, 34%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.38-7.34 (m, 3H), 7.22-7.20 (m, 2H), 6.94-6.84 (m, 2H), 5.57-5.53 (m, 1H), 5.07-5.02 (m, 1H), 4.66-4.62 (m, 1H), 4.50-4.47 (m, 1H), 3.25-3.15 (m, 1H), 3.13-3.03 (m, 2H), 2.69-2.66 (m, 1H). LCMS R_(T)=0.800 min, m/z=426.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.800 min, ESI+ found [M+H]=426.0.

Example 612

(5S)-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 103. The crude was purified by RP-HPLC (40% to 70% acetonitrile/0.05% ammonia hydroxide in water) to afford (5S)-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4, 5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (36.7 mg, 57%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.40-7.33 (m, 3H), 7.21-7.20 (m, 2H), 7.01-6.97 (m, 2H), 5.55-5.52 (m, 1H), 4.57-4.52 (m, 1H), 3.24-2.95 (m, 4H), 2.82-2.81 (m, 1H), 2.67-2.62 (m, 2H), 2.23-2.17 (m, 1H). LCMS R_(T)=0.798 min, m/z=424.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.798 min, ESI+ found [M+H]=424.1.

Example 613

(5S)-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 103. The crude was purified by RP-HPLC (38% to 68% acetonitrile/0.05% ammonia hydroxide in water) to afford (5S)-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (22.5 mg, 39%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.40-7.30 (m, 6H), 7.29-7.20 (m, 3H), 5.54 (t, J=6.8 Hz, 1H), 4.98-4.95 (m, 1H), 4.58-4.54 (m, 1H), 4.40-4.35 (m, 1H), 3.39 (s, 3H), 3.27-3.24 (m, 1H), 3.14-3.04 (m, 2H), 2.67-2.65 (m, 1H). LCMS R_(T)=0.823 min, m/z=404.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.823 min, ESI+ found [M+H]=404.1.

Example 614

(5S)-5-phenyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 103. The crude was purified by RP-HPLC (22% to 52% acetonitrile/0.05% ammonia hydroxide in water) to afford (5S)-5-phenyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (27.6 mg, 47%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.51 (s, 1H), 7.38-7.34 (m, 3H), 7.22-7.20 (m, 2H), 6.29 (s, 1H), 5.55 (t, J=6.8 Hz, 1H), 4.51-4.38 (m, 2H), 4.26-4.25 (m, 1H), 3.34 (s, 3H), 3.26-3.24 (m, 1H), 3.14-3.04 (m, 2H), 2.88-2.83 (m, 1H), 2.67-2.65 (m, 1H), 2.28-2.23 (m, 1H). LCMS R_(T)=0.753 min, m/z=392.0 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.753 min, ESI+ found [M+H]=392.0.

Example 615

(5R)-5-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 108. The crude was purified by RP-HPLC (23% to 53% acetonitrile/0.05% ammonia hydroxide in water) to afford (5R)-5-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (16 mg, 26%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ7.41-7.23 (m, 3H), 7.23-7.21 (m, 2H), 6.10 (s, 1H), 5.56-5.52 (m, 1H), 4.53-4.48 (m, 1H), 4.29-4.19 (m, 2H), 3.31 (s, 3H), 3.26-3.24 (m, 1H), 3.15-3.05 (m, 2H), 2.85-2.81 (m, 1H), 2.67-2.60 (m, 1H), 2.25-2.21 (m, 4H). LCMS R_(T)=0.759 min; m/z=406.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.759 min, ESI+ found [M+H]=406.1.

Example 616 WX Method 155

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclobutan]-2-carboxamide

Step 1: 2′-chloro-5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidin]-5′-one

To a solution of 2,2,6,6-tetramethylpiperidine (26.7 g, 189.2 mmol) in tetrahydrofuran (300 mL) was added n-butyllithium (2.5 M in hexanes, 76.0 mL, 189.2 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 2-chloropyrimidine-5-carboxylic acid (10.0 g, 63.1 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and cyclobutanone (13.2 g, 189.2 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 16 h and quenched by addition of saturated ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% ethyl acetate in petroleum ether) to afford 2′-chlorospiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-5′-one (4.2 g, 32%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 2.84-2.72 (m, 2H), 2.66-2.57 (m, 2H), 2.29-2.16 (m, 1H), 2.15-2.03 (m, 1H).

Step 2: 2′-chloro-5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidin]-5′-ol

To a solution of 2′-chlorospiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-5′-one (1.0 g, 4.75 mmol) in toluene (5 mL) was added diisobutylaluminum hydride (14.2 mL, 14.2 mmol, 1.0 M in toluene) at −70° C. The resulting solution was stirred at −70° C. for 0.5 h and quenched by addition of saturated ammonium chloride (20 mL). The mixture was filtered and the filtrate was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate to give the crude 2′-chloro-5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidin]-5′-ol (850 mg, 84%) as a yellow oil. LCMS R_(T)=1.58 min, m/z=213.1 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.58 min, ESI+ found [M+H]=213.1.

Step 3: 2′-chloro-5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]

To a solution of 2′-chloro-5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidin]-5′-ol (850 mg, 4.0 mol) in dichloromethane (10 mL) was added trifluoroacetic acid (4.6 g, 40.0 mmol) at 0° C. The mixture was stirred for 30 min at 0° C. and triethylsilane (4.6 g, 39.98 mmol) was added. After addition, the mixture was stirred for 12 h at 25° C. and quenched by addition of saturated sodium bicarbonate (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 35% ethyl acetate in petroleum ether to afford 2′-chloro-5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine](200 mg, 32%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 5.00 (s, 2H), 2.50-2.40 (m, 4H), 2.14-2.00 (m, 1H), 1.91-1.79 (m, 1H). LCMS R_(T)=1.94 min, m/z=197.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.94 min, ESI+ found [M+H]=197.1.

Step 4: 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carbonitrile

To a solution of 2′-chloro-5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine] (200 mg, 1.02 mmol) in dimethyl sulfoxide (2 mL) and water (1 mL) was added 1,4-diazabicyclo[2.2.2]octane (143 mg, 1.27 mmol) and sodium cyanide (150 mg, 3.06 mmol). The reaction mixture was stirred at 25° C. for 16 h and diluted with water (15 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carbonitrile (200 mg, 94%) as a yellow oil, used as is in the next step.

Step 5: methyl 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylate

A mixture of 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carbonitrile (200 mg, 1.07 mmol) in methanol (5 mL) was added HCl (4N in methanol, 5 mL. The mixture was heated at 70° C. for 12 h and concentrated under reduced pressure to ice crude methyl 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylate (225 mg, 98%) as a yellow oil, used as is in the next step.

Step 6: 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylic acid

A mixture of methyl 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylate (220 mg, 1 mmol) and lithium hydroxyl hydrate (419 mg, 10 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 20° C. for 12 h. The organic solvent was evaporated under reduced pressure and the aqueous layer was adjusted to pH=2-3 by addition of 1N HCl. The mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude 5′H-spiro[cyclobutane-1,7′-furo[3,4-d]pyrimidine]-2′-carboxylic acid (150 mg, 73%) as a yellow solid. LCMS R_(T)=0.40 min, m/z=207.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 0.40 min, ESI+ found [M+H]=207.1.

Step 7: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclobutane]-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (30 mg, 0.16 mmol), spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclobutane]-2-carboxylic acid (35 mg, 0.17 mmol), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (45 mg, 0.23 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (32 mg, 0.23 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 25% to 55%/0.05% ammonium hydroxide in water) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclobutane]-2-carboxamide (25.1 mg, 41.9%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.78 (s, 1H), 7.43 (m, 1H), 7.35-7.20 (m, 3H), 5.13 (s, 2H), 5.08-4.99 (m, 1H), 4.71 (m, 1H), 4.43 (m, 1H), 3.44 (s, 3H), 2.59-2.47 (m, 4H), 2.35-2.20 (m, 1H), 1.92 (m, 1H).

LCMS R_(T)=1.65 min, m/z=381.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.65 min, ESI+ found [M+H]=381.1.

Example 617

N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclobutane]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 155. The crude was purified by RP-HPLC (acetonitrile 25% to 55%/0.05% ammonium hydroxide in water) to give N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclobutane]-2-carboxamide (22 mg, 38%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.79 (s, 1H), 6.99-6.80 (m, 2H), 5.22-5.06 (m, 3H), 4.81-4.75 (m, 1H), 4.59-4.47 (m, 1H), 2.61-2.45 (m, 4H), 2.35-2.21 (m, 1H), 1.92 (m, 1H). LCMS R_(T)=1.62 min, m/z=403.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.62 min, ESI+ found [M+H]=403.1.

Example 618

N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]spiro 5H-furo[3,4-d]pyrimidine-7,1′-cyclobutane]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 155. The crude was purified by RP-HPLC (acetonitrile 22% to 52%/0.05% ammonium hydroxide in water) to give N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclobutane]-2-carboxamide (17 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.78 (s, 1H), 7.07-6.98 (m, 2H), 5.13 (s, 2H), 4.70-4.57 (m, 1H), 3.08-2.96 (m, 1H), 2.89-2.75 (m, 2H), 2.59-2.47 (m, 4H), 2.33-2.19 (m, 2H), 1.97-1.87 (m, 1H). LCMS R_(T)=1.60 min, m/z=401.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.60 min, ESI+ found [M+H]=401.1.

Examples 619 and 620

(7S)-7-methyl-7-propyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide and (7R)-7-methyl-7-propyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method N. The obtained racemic compound was separated by chiral SFC to give:

(7S)-7-methyl-7-propyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide (Peak 1, retention time 2.196 min) (11.7 mg, 39%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.83 (s, 1H), 6.97-6.88 (m, 2H), 5.17-5.07 (m, 3H), 4.79-4.74 (m, 1H), 4.58-4.52 (m, 1H), 1.93-1.83 (m, 2H), 1.50-1.40 (m, 4H), 1.07-1.01 (m, 1H), 0.90-0.86 (m, 3H). LCMS R_(T)=0.815 min; m/z=419.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.815 min, ESI+ found [M+H]=419.0.

(7R)-7-methyl-7-propyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-5H-furo[3,4-d]pyrimidine-2-carboxamide (Peak 2, retention time 2.316 min), (8.7 mg, 29%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.83 (s, 1H), 6.97-6.88 (m, 2H), 5.17-5.07 (m, 3H), 4.79-4.74 (m, 1H), 4.58-4.52 (m, 1H), 1.93-1.83 (m, 2H), 1.50-1.40 (m, 4H), 1.07-1.01 (m, 1H), 0.89-0.86 (m, 3H). LCMS R_(T)=0.997 min; m/z=419.3 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.997 min, ESI+ found [M+H]=419.3.

SFC conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:methanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40° C.

Example 621

(5R)-5-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 108. The crude was purified by RP-HPLC (30% to 60% acetonitrile/0.05% ammonia hydroxide in water) to afford (5R)-5-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (18 mg, 27%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ7.41-7.35 (m, 3H), 7.23-7.21 (m, 2H), 6.92-6.84 (m, 2H), 5.57-5.53 (m, 1H), 5.07-5.03 (m, 1H), 4.67-4.65 (m, 1H), 4.63-4.48 (m, 1H), 3.27-3.25 (m, 1H), 3.14-3.13 (m, 1H), 3.08-3.06 (m, 1H), 2.70-2.67 (m, 1H). LCMS R_(T)=0.796 min; m/z=426.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.796 min, ESI+ found [M+H]=426.0

Example 622

(5R)-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 108. The crude was purified by RP-HPLC (26% to 56% acetonitrile/0.05% ammonia hydroxide in water) to afford (5R)-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (29 mg, 44%) as white solid.

¹H NMR (400 MHz, CD₃OD) δ7.40-7.34 (m, 3H), 7.22-7.21 (m, 2H), 7.00-6.98 (m, 2H), 5.56-5.52 (m, 1H), 4.60-4.53 (m, 1H), 3.27-3.25 (m, 1H), 3.12-3.10 (m, 1H), 3.07-3.05 (m, 1H), 2.96-2.93 (m, 1H), 2.85-2.82 (m, 1H), 2.66-2.63 (m, 2H), 2.21-2.16 (m, 1H).

LCMS R_(T)=0.797 min; m/z=424.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.797 min, ESI+ found [M+H]=424.0

Example 623 WX Method 108

(5R)-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: (5R)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic

To a solution of ethyl (5R)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (130 mg, 0.51 mmol) in tetrahydrofuran (2 mL)/methanol (2 mL)/water (1 mL) was added lithium hydroxide hydrate (127.2 mg, 3.03 mmol). The mixture was stirred at 25° C. for 1 h and diluted with water (10 mL). The solution was adjusted to pH=4-5 by addition of 1N HCl. The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude (5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (110 mg, 95%) as a light yellow solid, used as is in the next step.

Step 2: (5R)-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (30 mg, 0.16 mmol), (5R)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (30 mg, 0.16 mmol), N¹-((ethylimino)methyl ene)-N³,N³-di methylpropane-1,3-diamine hydrochloride (30 mg, 0.15 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (21 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile, 0.05% ammonia hydroxide in water) to afford (5R)-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (29 mg, 55%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.41-7.21 (m, 9H), 5.54 (t, J=6.8 Hz, 1H), 5.00-4.96 (m, 1H), 4.59-4.56 (m, 1H), 4.41-4.36 (m, 1H), 3.40 (s, 3H), 3.27-3.24 (m, 1H), 3.15-3.04 (m, 2H), 2.67-2.65 (m, 1H). LCMS R_(T)=0.801 min; m/z=404.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.801 min, ESI+ found [M+H]=404.1.

Example 624

(5R)-5-phenyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 108. The crude was purified by RP-HPLC (28% to 58% acetonitrile/0.05% ammonia hydroxide in water) to afford (5R)-5-phenyl-N-[(6S)-4-methy-5-oxo-7,8-dihydro-6H-pyrazolo[4-methyl-5-oxo-[1,5-a][1,3]diazepin-6-yl]-6, 7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (17.4 mg, 34%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ7.51 (s, 1H), 7.38-7.34 (m, 3H), 7.22-7.20 (m, 2H), 6.29 (s, 1H), 5.55 (t, J=6.8 Hz, 1H), 4.51-4.38 (m, 2H), 4.26-4.25 (m, 1H), 3.34 (s, 3H), 3.26-3.24 (m, 1H), 3.14-3.04 (m, 2H), 2.88-2.83 (m, 1H), 2.67-2.65 (m, 1H), 2.28-2.23 (m, 1H).

LCMS R_(T)=0.727 min; m/z=392.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.727 min, ESI+ found [M+H]=392.0.

Examples 625 and 626 WX Method 113

(7S)-7-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (7R)-7-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: 1-amino-3-phenylpyrrolidin-2-one

To a solution of tert-butyl N-(2-oxo-3-phenyl-pyrrolidin-1-yl)carbamate (1.4 g, 5.1 mmol) in ethyl acetate (20 mL) was added HCl (4N in ethyl acetate, 12.0 mL, 48.0 mmol). The mixture was stirred at 20° C. for 3 h and concentrated under reduced pressure. The residue was slowly quenched by addition of saturated sodium bicarbonate (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give crude 1-amino-3-phenyl-pyrrolidin-2-one (590 mg, 66%) as a white solid, used as is in the next step.

Step 2: ethyl 2-imino-2-((2-oxo-3-phenylpyrrolidin-1-yl)amino)acetate

To a solution of 1-amino-3-phenyl-pyrrolidin-2-one (590 mg, 3.35 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino-acetate (1458 mg, 10.04 mmol). The mixture was stirred at 40° C. for 12 h and concentrated under reduced pressure to obtain crude ethyl (2Z)-2-amino-2-(2-oxo-3-phenyl-pyrrolidin-1-yl)imino-acetate (1370 mg, 100%), used as is in the next step.

Step 3: ethyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A solution of ethyl (2Z)-2-amino-2-(2-oxo-3-phenyl-pyrrolidin-1-yl)imino-acetate (1370 mg, 4.98 mmol) in phosphorus oxychloride (5 mL) as stirred at 120° C. for 1 h. After cooled, the mixture was slowly quenched by addition of saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (390 mg, 31%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.14 (m, 5H), 4.45 (q, J=8.0 Hz, 4H), 4.40-4.36 (m, 1H), 4.26-4.23 (m, 1H), 3.29-3.22 (m, 1H), 2.78-2.70 (m, 1H), 1.40 (t, J=7.2 Hz, 3H). LCMS R_(T)=1.95 min, m/z=258.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.95 min, ESI+ found [M+H]=258.1.

Step 4: 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of ethyl (7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (340 mg, 1.32 mmol) and lithium hydroxide hydrate (555 mg, 13.22 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 20° C. for 12 h. The organic solvent was evaporated under reduced pressure and the aqueous residue was adjusted to pH=2-3 by addition of 20% HCl. The mixture was extracted with dichloromethane (5×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford the crude 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (260 mg, 85%) as a yellow solid used as is in the next step.

Step 5: (7S)-7-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (7R)-7-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of 7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (33 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (33 mg, 0.17 mmol), 1-hydroxybenzotriazole (29 mg, 0.21 mmol) and (3s)-3-amino-6,8-difluoro-3,5-dihydro-2H-1,5-benzoxazepin-4-one (28 mg, 0.13 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (22% to 52% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (40 mg, 72%) as a white solid.

The racemic material was separated by chiral SFC to give:

(7S)-7-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 1, retention time 6.694 min) (20 mg, 50%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ 7.38-7.33 (m, 2H), 7.31-7.26 (m, 3H), 6.96-6.89 (m, 1H), 6.88-685 (m, 1H), 5.08-5.04 (m, 1H), 4.68-4.64 (m, 1H), 4.56-4.37 (m, 3H), 4.32-4.23 (m, 1H), 3.26-3.25 (m, 1H), 2.78-2.66 (m, 1H). LCMS R_(T)=2.22 min, m/z=426.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 2.22 min, ESI+ found [M+H]=426.1.

(7R)-7-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 2, retention time 7.313 min) (19 mg, 48%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.29-7.22 (m, 2H), 7.21-7.14 (m, 3H), 6.87-6.79 (m, 1H), 6.78-6.75 (m, 1H), 4.98-4.94 (m, 1H), 4.58-4.56 (m, 1H), 4.48-4.27 (m, 3H), 4.32-4.19 (m, 1H), 3.18-3.14 (m, 1H), 2.67-2.56 (m, 1H). LCMS RT=2.23 min, m/z=426.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 2.23 min, ESI+ found [M+H]=426.2.

SFC conditions: Column: Chiralcel AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% dethyl acetate), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature: 40° C.

Examples 627 and 628

(7S)-7-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (7R)-7-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 113. The racemic material (70 mg) was separated by chiral SFC to give:

(7S)-7-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 1, retention time=6.794 min) (34.1 mg, 48.2%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.37-7.26 (m, 5H), 7.02-6.98 (m, 2H), 4.60-4.51 (m, 2H), 4.43-4.40 (m, 1H), 4.30-4.27 (m, 1H), 3.30-3.27 (m, 1H), 2.98-2.96 (m, 1H), 2.83-2.81 (m, 1H), 2.71-2.63 (m, 2H), 2.21-2.19 (m, 1H). LCMS R_(T)=1.730 min, m/z=424.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.730 min, ESI+ found [M+H]=424.1.

(7R)-7-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 2, retention time=7.082 min) (32.5 mg, 46%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.37-7.33 (m, 2H), 7.32-7.26 (m, 3H), 7.01-6.98 (m, 2H), 4.59-4.50 (m, 2H), 4.45-4.40 (m, 1H), 4.27-4.25 (m, 1H), 3.30-3.27 (m, 1H), 2.98-2.96 (m, 1H), 2.83-2.81 (m, 1H), 2.71-2.63 (m, 2H), 2.22-2.19 (m, 1H). LCMS R_(T)=1.730 min, m/z=424.1 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.730 min, ESI+ found [M+H]=424.1.

SFC condition: column: chiralpak AD-3 (250 mm*30 mm, 5 um), 3 um mobile phase: A:CO2; B: EtOH (0.05% DEA) gradient: from 5 to 40 of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example 629 WX Method 125

(8R)-8-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

Step 1: (3-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-H-1,2,4-triazol-5-yl)(2-fluorophenyl) methanol

To a solution of 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2.0 g, 5.6 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h and then a solution of 2-fluorobenzaldehyde (1.4 g, 11.27 mmol) in THF (2 mL) was added. After addition, the mixture was stirred at −78° C. for another 1 h and then quenched by addition of saturated ammonium chloride (10 mL). The resulting mixture was diluted with ethyl acetate (100 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-(2-fluorophenyl)methanol (1.0 g, 44%) as a light yellow oil. LCMS R_(T)=0.64 min, m/z=401.7 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.64 min, ESI+ found [M+H]=401.7.

Step 2: 2-bromo-8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A mixture of [5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-(2-fluorophenyl)methanol (1000 mg, 2.5 mmol) and p-toluenesulfonic acid (546 mg, 3.17 mmol) in toluene (20 mL) was heated at reflux for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give 2-bromo-8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine (300 mg, 40.3%) as yellow solid, used as is in the next step.

Step 3: Methyl 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate

A mixture of 2-bromo-8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine (290 mg, 0.97 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (13 mg, 0.02 mmol). and triethylamine (1.31 mL, 9.73 mmol) in methanol (10 mL) was heated at 80° C. for 16 h under CO (25 psi) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 100% dichloromethane) to give methyl 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate (200 mg, 74%) as colorless oil. LCMS R_(T)=0.59 min, m/z=277.8 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.59 min, ESI+ found [M+H]=277.8.

Step 4: 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid

A mixture of methyl 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate (200 mg, 0.72 mmol) and potassium hydroxide (80 mg, 1.44 mml) in ethanol (20 mL) and water (5 mL) was stirred at 25° C. for 1 h. The ethanol was evaporated under reduced pressure and the aqueous residue was adjusted to pH=3 by addition of 2N HCl. The solution was extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated to give crude 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid (180 mg, 94%) as a yellow solid, used as is in the next step.

Step 5: (8R)-8-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (50 mg, 0.26 mmol), 8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylic acid (102 mg, 0.39 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (49 mg, 0.26 mmol) and 1-hydroxybenzotriazole (7 mg, 0.05 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (36% to 66% acetonitrile/0.05% ammonia hydroxide in water) to give 8-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6, 8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (60 mg, 53%) as a white solid. The racemic material was separated by chiral SFC to give:

(8R)-8-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,8-di hydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 2, retention time 1.825 min) (33 mg, 54.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 2H), 7.45-7.39 (m, 1H), 7.34-7.20 (m, 5H), 6.18 (s, 1H), 4.86-4.77 (m, 1H), 4.61-4.55 (m, 1H), 4.45-4.32 (m, 4H), 4.25-4.17 (m, 1H), 3.29 (s, 3H). LCMS R_(T)=0.80 min, m/z=438.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.80 min, ESI+ found [M+H]=438.1.

SFC: Column: Chiralcel AD-3 50×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min Column temp.: 40° C.

Example 630

(8S)-8-(2-fluorophenyl)-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 125. The crude was purified by RP-HPLC (35% to 75% acetonitrile/0.05% ammonia hydroxide in water) to give N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-8-(2-fluorophenyl)-6, 8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (60 mg, 53%) as a white solid. The racemic material (30 mg) was separated by chiral SFC to give:

(8S)-8-(2-fluorophenyl)-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6, 8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 2, retention time 1.588 min) (30 mg, 49.5%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.47-7.41 (m, 1H), 7.37-7.32 (m, 1H), 7.23-7.12 (m, 2H), 7.01-6.94 (m, 3H), 6.13 (s, 1H), 4.57-4.33 (m, 4H), 4.27-4.18 (m, 1H), 3.00-2.89 (m, 1H), 2.72-2.75 (m, 1H), 2.64-2.53 (m, 1H), 2.23-2.15 (m, 1H). LCMS R_(T)=0.79 min, m/z=458.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.79 min, ESI+ found [M+H]=458.1.

SFC conditions: Column: Chiralcel AD-3 50×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min Column temp.: 40° C.

Example 631 WX Method 138

1-(2-pyridyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Step 1: N—[(Z)-(2,4,6-trichloropyrimidin-5-yl)methyleneamino]pyridin-2-amine

To a solution of 2,4,6-trichloro-5-pyrimidinecarboxaldehyde (1.0 g, 4.73 mmol) in N,N-dimethylformamide (5 mL) was added 2-hydrazinopyridine (530 mg, 4.86 mmol). The mixture was stirred at 20° C. for 12 h and added water (20 mL), saturated sodium bicarbonate (10 mL). The resulting solid was collected by filtration and dried under reduced pressure to afford N—[(Z)-(2,4,6-trichloropyrimidin-5-yl) methyleneamino]pyridin-2-amine (900 mg, 63%) as a brown solid, used as is in the next step.

Step 2: 4,6-dichloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine

A solution of N—[(Z)-(2,4,6-trichloropyrimidin-5-yl)methyleneamino]pyridin-2-amine (820 mg, 2.71 mmol) in acetonitrile (30 mL) was stirred at 110° C. for 6 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford 4,6-dichloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine (550 mg, 76%) as a white solid, used as is in the next step.

Step 3: 6-chloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine

To a mixture of 4,6-dichloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine (550 mg, 2.07 mmol) and zinc (418 mg, 6.39 mmol) in tetrahydrofuran (20 mL) was added ammonium hydroxide (20 mL) at 0° C. The reaction mixture was stirred for 1.5 h and adjusted to pH=9 by addition of saturated sodium bicarbonate. The mixture was filtered and the filtrate was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=1:1, R_(f)=0.2) to afford 6-chloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine (270 mg, 56%) as a light yellow solid, used as is in the next step.

Step 4: methyl 1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine-6-carboxylate

A mixture of 6-chloro-1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine (180 mg, 0.78 mmol), triethylamine (0.88 mL, 6.32 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (57 mg, 0.08 mmol) in methanol (20 mL) was heated at 70° C. under CO (35 psi) for 20 h and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by preparative TLC (ethyl acetate, R_(f)=0.2) to afford methyl 1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine-6-carboxylate (120 mg, 61%) as a brown oil, used as is in the next step.

Step 6: 1-(2-pyridyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (23 mg, 0.12 mmol), methyl 1-(2-pyridyl)pyrazolo[3,4-d]pyrimidine-6-carboxylate (30 mg, 0.12 mmol) in toluene (10 mL) was added trimethylaluminum (0.2 mL, 0.40 mol) in toluene (10 mL). The mixture was heated at 110° C. for 12 h and then quenched by addition of methanol (5 mL). The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (dichloromethane methane=10:1, R_(f)=0.5) to afford 1-(2-pyridyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (5 mg, 9.8%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 9.53 (s, 1H), 8.68 (s, 1H), 8.65 (d, J=4.0 Hz, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.19-8.12 (m, 1H), 7.54-7.50 (m, 1H), 7.48-7.44 (m, 1H), 7.36-7.30 (m, 2H), 7.28-7.25 (m, 1H), 5.12-5.07 (m, 1H), 4.73-4.69 (m, 1H), 4.55-4.47 (m, 1H), 3.45 (s, 3H). LC-MS R_(T)=0.757 min, m/z=416.0 (M+H)⁺

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.757 min, ESI+ found [M+H]=416.0.

Examples 632 and 633

1-(2-pyridyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide and 1-(2-pyridyl)-N-[(6R)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide

Ester-amide exchange prepared in a similar fashion to WX Method 138. The racemic compound was separated by chiral SFC to give arbitrarily assigned enantiomers:

1-(2-pyridyl)-N-[1(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (Peak 1, retention time 1.70 min) (14.5 mg, 47%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ9.53 (s, 1H), 8.68 (s, 1H), 8.64 (d, J=4.0 Hz, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.18-8.11 (m, 1H), 7.55-7.50 (m, 1H), 6.14 (s, 1H), 4.66-4.59 (m, 1H), 4.36-4.27 (m, 2H), 3.37 (s, 3H), 3.02-2.92 (m, 1H), 2.39-2.31 (m, 1H), 2.27 (s, 3H). LC-MS R_(T)=0.712 min, m/z=418.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.712 min, ESI+ found [M+H]=418.0.

1-(2-pyridyl)-N-[(6R)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide (Peak 2, retention time 2.07 min) (5.0 mg, 16%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ9.52 (s, 1H), 8.68 (s, 1H), 8.64 (s, 1H), 8.48 (d, J=8.4 Hz, 1H), 8.14 (t, J=7.2 Hz, 1H), 7.56-7.49 (m, 1H), 6.14 (s, 1H), 4.67-4.59 (m, 1H), 4.41-4.25 (m, 2H), 3.37 (s, 3H), 3.01-2.93 (m, 1H), 2.38-2.29 (m, 1H), 2.27 (s, 3H).

LC-MS R_(T)=0.709 min, m/z=418.0 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.709 min, ESI+ found [M+H]=418.0.

SFC condition: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: A:CO₂ B:ethanol (0.05% DEA) Gradient: hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min Flow rate: 4 mL/min Column temp: 40° C.

Example 634

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydropyrrol[1,2-b][1,2,4]triazole-7,4′-tetrahydropyran]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 129. The crude was purified by RP-HPLC (22% to 52% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,4′-tetrahydropyran]-2-carboxamide (15 mg, 56%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.46-7.40 (m, 1H), 7.36-7.27 (m, 2H), 7.25-7.21 (m, 1H), 5.03-4.98 (m, 1H), 4.62-4.58 (m, 1H), 4.45-4.39 (m, 1H), 4.27-4.23 (m, 2H), 4.08-4.00 (m, 2H), 3.79-3.70 (m, 2H), 3.42 (s, 3H), 2.71-2.67 (m, 2H), 1.97-1.87 (m, 2H), 1.82-1.70 (m, 2H).

LCMS R_(T)=1.58 min, m/z=398.3 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.58 min, ESI+ found [M+H]=398.3.

Example 635 WX Method 131

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,4′-tetrahydropyran]-2-carboxamide

Step 1: ethyl 4-allyltetrahydropyran-4-carboxylate

To a solution of ethyl tetrahydropyran-4-carboxylate (10.0 g, 63.22 mmol) in tetrahydrofuran (200 mL) was added lithium diisopropylazanide (2N in tetrahedron, 32.91 mL, 65.81 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 min and then allyl bromide (9.2 g, 75.86 mmol) was added. The reaction mixture was stirred at 20° C. for 16 h and quenched by addition of saturated ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude ethyl 4-allyltetrahydropyran-4-carboxylate (9.0 g, 72%) as a yellow oil, used as is in the next step.

Step 2: ethyl 4-(2-oxoethyl)tetrahydropyran-4-carboxylate

A mixture of ethyl 4-allyltetrahydropyran-4-carboxylate (9.0 g, 45.39 mmol), osmium tetroxide (500 mg, 1.97 mmol) and sodium periodate (14.5 g, 68.09 mmol) in tetrahydrofuran (100 mL) and water (100 mL) was stirred at 20° C. for 2 h. The mixture was quenched by addition of water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl 4-(2-oxoethyl)tetrahydropyran-4-carboxylate (4.0 g, 44%) as a yellow oil, used as is in the next step.

Step 3: tert-butyl N-(1-oxo-8-oxa-2-azaspiro[4.5]decan-2-yl)carbamate

To a solution of ethyl 4-(2-oxoethyl)tetrahydropyran-4-carboxylate (4.0 g, 19.98 mmol) in acetic acid (20 mL) and tetrahydrofuran (40 mL) was added tert-butyl hydrazinecarboxylate (3.17 g, 23.97 mmol). The reaction mixture was stirred at 20° C. for 2 h and sodium cynoborohydride (3.77 g, 59.93 mmol) was added. The reaction mixture was heated at 50° C. for 6 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (17% to 47% acetonitrile/0.05% ammonia hydroxide in water) to afford tert-butyl N-(1-oxo-8-oxa-2-azaspiro[4.5]decan-2-yl)carbamate (1.0 g, 18%) as a white solid, used as is in the next step.

Step 4: 2-amino-8-oxa-2-azaspiro[4.5]decan-1-one hydrochloride

To a solution of tert-butyl N-(1-oxo-8-oxa-2-azaspiro[4.5]decan-2-yl)carbamate (200 mg, 0.74 mmol) in ethyl acetate (5 mL) was added HCl (4N in ethyl acetate, 10.0 mL, 40.0 mmol). The mixture was stirred at 35° C. for 12 h and concentrated under reduced pressure to afford crude 2-amino-8-oxa-2-azaspiro[4.5]decan-1-one (120 mg, 95%) as a yellow oil, used as is in the next step.

Step 5: (Z)-ethyl 2-amino-2-((2-oxo-8-oxa-1-azaspiro[4.5]decan-1-yl)imino)acetate

To a solution of 2-amino-8-oxa-2-azaspiro[4.5]decan-1-one hydrochloride (100 mg, 0.59 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino-acetate (256 mg, 1.76 mmol). The mixture was stirred at 30° C. for 12 h and concentrated under reduced pressure to give crude ethyl(2Z)-2-amino-2-[(2-oxo-8-oxa-1-azaspiro[4.5]decan-1-yl)imino]acetate (130 mg, 82%) as a yellow oil. LCMS R_(T)=1.43 min, m/z=270.1 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.43 min, ESI+ found [M+H]=270.1

Step 6: ethyl 2,3,5,5′,6,6′-hexahydrospiro[pyran-4,7′-pyrrolo[1,2-b][1,2,4]triazole]-2′-carboxylate

A mixture of (Z)-2-amino-2-[(2-oxo-8-oxa-1-azaspiro[4.5]decan-1-yl)imino]acetate (180 mg, 0.67 mmol) and phosphorus oxychloride (5 mL, 53.28 mmol) in ethyl acetate (10 mL) was heated at 120° C. for 1 h and cooled. The mixture was slowly quenched by addition of water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with 20% sodium bicarbonate (20 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% ethyl acetate in petroleum ether) to afford ethyl spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,4′-tetrahydropyran]-2-carboxylate (85 mg, 51%) as a light yellow oil, used as is in the next step.

Step 7: 2,3,5,5′,6,6′-hexahydrospiro[pyran-4,7′-pyrrolo[1,2-b][1,2,4]triazole]-2′-carboxylic acid

A mixture of ethyl spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,4′-tetrahydropyran]-2-carboxylate (80 mg, 0.32 mmol) and lithium hydroxide (153 mg, 6.37 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at 20° C. for 12 h. After evaporation of the organic solvent, the mixture was adjusted to pH=6 by addition of 1N HCl. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated under reduced pressure to give crude spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,4′-tetrahydropyran]-2-carboxylic acid (60 mg, 84%) as a yellow oil, used as is in the next step.

Step 8: N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,4′-tetrahydropyran]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 129. The crude was purified by RP-HPLC (22% to 52% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxamide (6.7 mg, 18.5%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ6.11 (s, 1H), 4.59-4.49 (m, 1H), 4.37-4.16 (m, 4H), 4.06-4.02 (m, 2H), 3.80-3.68 (m, 2H), 3.33 (s, 3H), 2.86-2.84 (m, 1H), 2.74-2.65 (m, 2H), 2.30-2.21 (m, 4H), 1.99-1.88 (m, 2H), 1.82-1.71 (m, 2H). LCMS R_(T)=1.13 min, m/z=400.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.13 min, ESI+ found [M+H]=400.2.

Example 636 WX Method 134

4-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-amine

To a solution of aniline (329 mg, 3.54 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (1N in tetrahedron, 12.86 mL, 12.86 mmol), and then 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (500 mg, 1.61 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 h and quenched by addition of saturate ammonium chloride (10 mL). The mixture was extracted with dichloromethane (2×20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to afford 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-amine (500 mg, 96%) as a yellow solid, used as is in the next step.

Step 2: 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1,2,4-triazol-5-amine

To a solution of sodium iodide (232 mg, 1.55 mmol) and 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-amine (500 mg, 1.55 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, 62 mg, 1.55 mmol). The reaction mixture was stirred at 50° C. for 0.5 hour, then 2-(2-bromoethoxy)tetrahydro-2H-pyran (408 mg, 1.95 mmol) was added. After addition, the mixture was stirred at 50° C. for another 15 h and then diluted with ice water (5 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1,2,4-triazol-5-amine (500 mg, 72%) as yellow oil, used as is in the next step.

Step 3: 2-((3-bromo-1H-1,2,4-triazol-5-yl)(phenyl)amino)ethanol

A mixture of 3-bromo-N-phenyl-1-(tetrahydro-2H-pyran-2-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1,2,4-triazol-5-amine (500 mg, 1.11 mmol) and 2,2,2-trifluoroacetic acid (126 mg, 1.11 mmol) in dichloromethane (10 mL) was stirred at 15° C. for 15 h and concentrated under reduced pressure to afford crude 2-(N-(3-bromo-1H-1,2,4-triazol-5-yl)-2,6-difluoro-anilino)ethanol (200 mg, 64%) as a brown oil. LCMS R_(T)=1.315 min, m/z=283.2 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.315 min, ESI+ found [M+H]=283.2.

Step 4: 3-bromo-N-(2-bromoethyl)-N-phenyl-1H-1,2,4-triazol-5-amine

A mixture of 2-(N-(3-bromo-1H-1,2,4-triazol-5-yl)-2,6-difluoro-anilino)ethanol (100 mg, 0.35 mmol) and phosphoryl tribromide (101 mg, 0.35 mmol) in acetonitrile (5 mL) was heated at 50° C. for 15 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to afford 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 82%) as a brown oil. LCMS R_(T)=0.719 min, m/z=346.8 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.719 min, ESI+ found [M+H]=346.8.

Step 5: 2-bromo-4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole

A mixture of 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazol-5-amine (90 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 15 h and then diluted with ice water (3 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford 2-bromo-4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole (50 mg, 73%) as a white solid, used as is in the next step.

Step 6: methyl 4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of 2-bromo-4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole (50 mg, 0.19 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichlororide (13 mg, 0.02 mmol) and triethylamine (191 mg, 1.88 mmol) in methanol (40 mL) was heated at 70° C. for 12 h under CO (40 psi) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford methyl 4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylate (45 mg, 98%) as a yellow solid. LCMS R_(T)=1.535 min, m/z=245.3 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.535 min, ESI+ found [M+H]=245.3.

Step 7: 4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of methyl 4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylate (40 mg, 0.16 mmol) and lithium hydroxide (20 mg, 0.82 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred at 25° C. for 15 h. The reaction mixture was adjusted to pH=3 by addition of 1N HCl and concentrated under reduced pressure to afford crude 4-phenyl-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylic acid (40 mg, 93%) as a yellow solid. LCMS R_(T)=1.309 min, m/z=230.9 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 1.309 min, ESI+ found [M+H]=230.9.

Step 8: 4-phenyl-N-1[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of 4-phenyl-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxylic acid (40 mg, 0.17 mmol), (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (33 mg, 0.17 mmol), 1-hydroxybenzotriazole (56 mg, 0.42 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (80 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile/0.05% HCl in water) to afford 4-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxamide (3.5 mg, 5%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.58 (d, J=8.0 Hz, 2H), 7.41-7.37 (m, 2H), 7.06-7.02 (m, 1H), 6.15 (s, 1H), 4.63-4.51 (m, 3H), 4.48-4.41 (m, 2H), 4.33 (s, 1H), 4.29-4.23 (m, 1H), 3.35 (s, 3H), 2.91-2.84 (m, 1H), 2.38-2.21 (m, 4H). LCMS R_(T)=0.752 min, m/z=407.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.752 min, ESI+ found [M+H]=407.1

Example 637

N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 164. The crude was purified by RP-HPLC (acetonitrile 38% to 68%/0.05% ammonium hydroxide in water) to give N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]spiro[5H-furo[3,4-d]pyrimidine-7,1′-cyclopentane]-2-carboxamide (30.3 mg, 51%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 7.06-7.00 (m, 2H), 5.11 (s, 2H), 4.65-4.60 (m, 1H), 3.07-2.98 (m, 1H), 2.86-2.76 (m, 2H), 2.27-2.22 (m, 1H), 2.10-2.00 (m, 4H), 1.98-1.87 (m, 4H). LCMS R_(T)=0.714 min, m/z=414.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.05% ammonium hydroxide over 1.5 mins) retention time 0.714 min, ESI+ found [M+H]=414.9.

Examples 638 and 639

(8S)-8-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide and (8R)-8-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 121. The racemic material (30 mg) was separated by chiral SFC to give:

(8S)-8-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 1, retention time 4.962 min) (9.4 mg, 31%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.46-7.34 (m, 5H), 7.04-6.96 (m, 2H), 5.94 (s, 1H), 4.59-4.52 (m, 1H), 4.50-4.43 (m, 1H), 4.40-4.33 (m, 2H), 4.25-4.17 (m, 1H), 3.01-2.91 (m, 1H), 2.84-2.76 (m, 1H), 2.66-2.55 (m, 1H), 2.26-2.14 (m, 1H). LCMS R_(T)=0.955 min, m/z=440.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.955 min, ESI+ found [M+H]=440.2

(8R)-8-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 2, retention time 5.392 min) (8.8 mg, 29%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.46-7.34 (m, 5H), 7.03-6.95 (m, 2H), 5.94 (s, 1H), 4.60-4.52 (m, 1H), 4.50-4.43 (m, 1H), 4.40-4.32 (m, 2H), 4.25-4.16 (m, 1H), 3.01-2.91 (m, 1H), 2.84-2.76 (m, 1H), 2.66-2.54 (m, 1H), 2.24-2.13 (m, 1H). LCMS R_(T)=0.955 min, m/z=440.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.955 min, ESI+ found [M+H]=440.2

SFC condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature: 40° C.

Examples 640 and 641

(8S)-8-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide and (8R)-8-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 121. The crude was purified by RP-HPLC (17% to 47% acetonitrile/0.05% ammonia hydroxide in water) to afford N—((S)-6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (40 mg, 42%). The racemic material was separated by chiral SFC to give:

(8S)-8-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 1, retention time 4.810 min) (7.7 mg, 19%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ7.45-7.35 (m, 5H), 6.96-6.89 (m, 1H), 6.88-6.82 (m, 1H), 5.95 (s, 1H), 5.09-5.01 (m, 1H), 4.68-4.60 (m, 1H), 4.51-4.46 (m, 2H), 4.42-4.33 (m, 2H), 4.26-4.17 (m, 1H). LCMS R_(T)=0.956 min, m/z=442.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.956 min, ESI+ found [M+H]=442.1.

(8R)-8-phenyl-N-[(3S)-6,8-difluoro-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 2, retention time 5.392 min) (7.9 mg, 19%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ7.47-7.33 (m, 5H), 6.97-6.89 (m, 1H), 6.85 (d, J=9.6 Hz, 1H), 5.95 (s, 1H), 5.09-5.01 (m, 1H), 4.66-4.59 (m, 1H), 4.52-4.44 (m, 2H), 4.40-4.33 (m, 2H), 4.26-4.17 (m, 1H). LCMS R_(T)=0.961 min, m/z=442.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.961 min, ESI+ found [M+H]=442.1

SFC condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature: 40° C.

Examples 42 rd 43

(8S)-8-phenyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide and (8R)-8-phenyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 121. The racemic material (30 mg) was separated by chiral SFC to give:

(8S)-8-phenyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 1, retention time 5.076 min) (10.9 mg, 36%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ7.44-7.36 (m, 5H), 6.89-6.83 (m, 2H), 5.94 (s, 1H), 5.06-4.98 (m, 1H), 4.63-4.56 (m, 1H), 4.52-4.33 (m, 5H), 4.25-4.17 (m, 1H), 2.33 (s, 3H). LCMS R_(T)=0.988 min, m/z=438.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.988 min, ESI+ found [M+H]=438.2

(8R)-8-phenyl-N-[(3S)-6-fluoro-8-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxamide (Peak 2, retention time 5.374 min) (11 mg, 37%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ7.44-7.36 (m, 5H), 6.90-6.82 (m, 2H), 5.95 (s, 1H), 5.06-4.98 (m, 1H), 4.62-4.55 (m, 1H), 4.52-4.33 (m, 5H), 4.25-4.17 (m, 1H), 2.33 (s, 3H). LCMS R_(T)=0.994 min, m/z=438.1 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.994 min, ESI+ found [M+H]=438.1

SFC condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 644

1-[(3-methyl-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 019. The crude was purified by RP-HPLC (acetonitrile 13-43%/0.05% ammonium hydroxide in water) to give 1-[(3-methyl-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (8.0 mg, 15%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.57 (s, 1H), 8.32 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.28-7.27 (m, 1H), 6.10 (s, 1H), 5.63 (s, 2H), 4.54-4.49 (m, 1H), 4.33-4.20 (m, 2H), 3.30 (s, 3H), 2.85-2.83 (m, 1H), 2.46 (s, 3H), 2.25-2.23 (m, 4H). LC-MS R_(T)=1.258 min, m/z=395.1 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.258 min, ESI+ found [M+H]=395.1.

Example 645 WX Method 129

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxamide

Step 1: methyl 3-allyltetrahydrofuran-3-carboxylate

To a solution of methyl tetrahydrofuran-3-carboxylate (2.6 g, 19.98 mmol) in tetrahydrofuran (10 mL) was added sodium bis(trimethylsilyl)azanide (1N in tetrahydrofuran, 20.0 mL, 20.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 min and then allyl iodide (5.0 g, 29.77 mmol) was added. The reaction mixture was stirred at −78° C. for another 15 min and then quenched by addition of saturated ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford methyl 3-allyltetrahydrofuran-3-carboxylate (1.9 g, 56%) as yellow oil, used in the next step as is.

Step 2: methyl 3-(2-oxoethyl)tetrahydrofuran-3-carboxylate

A mixture of methyl 3-allyltetrahydrofuran-3-carboxylate (1.9 g, 11.16 mmol), osmium tetroxide (100 mg, 0.39 mmol) and sodium periodate (4.77 g, 22.33 mmol) in tetrahydrofuran (30 mL) and water (30 mL) was stirred at 20° C. for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford methyl 3-(2-oxoethyl)tetrahydrofuran-3-carboxylate (1.0 g, 57%) as yellow oil, used in the next step as is.

Step 3: tert-butyl (6-oxo-2-oxa-7-azaspiro[4.4]nonan-7-yl)carbamate

To a solution of methyl 3-(2-oxoethyl)tetrahydrofuran-3-carboxylate (1.1 g, 6.39 mmol) in acetic acid (7.5 mL) and tetrahydrofuran (15 mL) was added tert-butyl hydrazinecarboxylate (1.01 g, 7.67 mmol). The reaction mixture was stirred at 20° C. for 2 h and sodium cyanoborohydride (1.2 g, 19.17 mmol) was added. The reaction mixture was heated at 50° C. for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to afford tert-butyl N-(1-oxo-7-oxa-2-azaspiro[4.4]nonan-2-yl)carbamate (500 mg, 31%) as white solids, used in the next step as is.

Step 4: 7-amino-2-oxa-7-azaspiro[4.4]nonan-6-one

To a solution of tert-butyl N-(1-oxo-7-oxa-2-azaspiro[4.4]nonan-2-yl)carbamate (500 mg, 1.95 mmol) in ethyl acetate (10 mL) was added HCl (4N in ethyl acetate, 5.0 mL, 20 mmol). The reaction mixture was stirred at 15° C. for 4 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and adjusted to pH=10 by addition of saturated sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (8×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-amino-7-oxa-2-azaspiro[4.4]nonan-1-one (200 mg, 66%) as a yellow oil, used in the next step as is.

Step 5: (Z)-ethyl 2-amino-2-((6-oxo-2-oxa-7-azaspiro[4.4]nonan-7-yl)imino)acetate

To a solution of 2-amino-7-oxa-2-azaspiro[4.4]nonan-1-one (200 mg, 1.28 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino-acetate (929 mg, 6.40 mmol). The mixture was heated at 40° C. for 12 h and concentrated under reduced pressure to afford crude ethyl (2Z)-2-amino-2-[(2-oxo-7-oxa-1-azaspiro[4.4]nonan-1-yl)imino]acetate (150 mg, 46%) as yellow oil, used in the next step as is.

Step 6: ethyl spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxylate

A solution of ethyl (2Z)-2-amino-2-[(2-oxo-7-oxa-1-azaspiro[4.4]nonan-1-yl)imino]acetate (150 mg, 0.59 mmol) in phosphorus oxychloride (5 mL, 56.09 mmol) was heated at 120° C. for 1 h and cooled. The mixture was slowly quenched by addition of water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with 20% sodium bicarbonate (20 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% ethyl acetate in petroleum ether) to afford ethyl spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxylate (80 mg, 57%) as light yellow oil, used in the next step as is.

Step 7: spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxylic acid

A mixture of ethyl spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxylate (80 mg, 0.34 mmol) and lithium hydroxide monohydrate (141 mg, 3.37 mmol) in tetrahydrofuran (5 mL) and water (3 mL) was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure and diluted with water (10 mL). The solution was adjusted to pH=5 by addition of 1N HCl (5 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic layers were concentrated under reduced pressure to afford crude spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxylic acid (40 mg, 57%) as a yellow solid, used in the next step as is.

Step 8: N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxamide

A mixture of spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxylic acid (20 mg, 0.10 mmol), 1-hydroxybenzotriazole (25 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (40 mg, 0.21 mmol), and (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (18 mg, 0.10 mmol) in N,N-Dimethylformamide (5 mL) was stirred at 15° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 32-62%/0.05% ammonium hydroxide in water) to afford N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxamide (8.6 mg, 23%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.43 (d, J=6.8 Hz, 1H), 7.33-7.30 (m, 2H), 7.23 (d, J=6.0 Hz, 1H), 5.00-4.84 (m, 1H), 4.61-4.57 (m, 1H), 4.43-4.40 (m, 1H), 4.26 (t, J=6.8 Hz, 2H), 4.13-4.09 (m, 1H), 4.03-4.00 (m, 1H), 3.95-3.91 (m, 1H), 3.88-3.85 (m, 1H), 3.42 (s, 3H), 2.85-2.79 (m, 2H), 2.40-2.35 (m, 1H), 2.21-2.18 (m, 1H). LCMS R_(T)=0.713 min; m/z=384.0 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.713 min, ESI+ found [M+H]=384.0.

Example 646

N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 129. The crude was purified by RP-HPLC (28% to 58% acetonitrile/0.05% ammonia hydroxide in water) to afford N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]spiro[5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-7,3′-tetrahydrofuran]-2-carboxamide (5.9 mg, 16%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ6.11 (s, 1H), 4.54-4.52 (m, 1H), 4.53-4.24 (m, 4H), 4.15-4.10 (m, 1H), 4.05-4.01 (m, 1H), 3.94-3.92 (m, 1H), 3.89-3.86 (m, 1H), 3.33 (s, 3H), 2.85-2.79 (m, 3H), 2.40-2.35 (m, 1H), 2.26 (s, 3H), 2.24-2.19 (m, 2H). LCMS R_(T)=0.626 min; m/z=386.0 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.626 min, ESI+ found [M+H]=386.0.

Example 647 WX Method 019

1-[(3-methyl-2-pyridyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazol-3-carboxamide

Step 1: methyl 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (200 mg, 1.57 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (435 mg, 3.15 mmol) and 2-(chloromethyl)-3-methylpyridine (223 mg, 1.57 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (150 mg, 41%) as a colorless oil. LC-MS R_(T)=0.302 min, m/z=232.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.302 min, ESI+ found M+H 232.9.

Step 2: 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (100 mg, 0.43 mmol) and lithium hydroxide hydrate (90 mg, 2.15 mmol) in tetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25° C. for 2 h. The solution was diluted with water (10 mL) and adjusted to pH=4-5 by addition of 1M HCl. The resulting solid was collected by filtration and dried under reduced pressure to give crude 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (90 mg, 96%) as a light yellow solid, used as is in the next step.

Step 3: 1-[(3-methyl-2-pyridyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a stirred solution of (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (25 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (29 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (39 mg, 0.21 mmol) and 1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (30 mg, 0.14 mmol). The mixture was stirred at 20° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 10-40%/0.05% ammonium hydroxide in water) to afford N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-[(3-methyl-2-pyridyl)methyl]-1,2,4-triazole-3-carboxamide (7 mg, 13%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.57 (s, 1H), 8.32 (d, J=4.8 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.30-7.26 (m, 1H), 6.30 (d, J=2.0 Hz, 1H), 5.63 (s, 2H), 4.52-4.39 (m, 2H), 4.32-4.28 (m, 1H), 3.35 (s, 3H), 2.89-2.84 (m, 1H), 2.45 (s, 3H), 2.28-2.24 (m, 1H). LC-MS R_(T)=1.135 min, m/z=381.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.135 min, ESI+ found [M+H]=381.2.

Example 648

1-[(3-methyl-2-pyridyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 019. The crude was purified by RP-HPLC (acetonitrile 18-48%/0.05% ammonium hydroxide in water) to give 1-[(3-methyl-2-pyridyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (7.4 mg, 13%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.58 (s, 1H), 8.33 (d, J=4.4 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.30-7.27 (m, 1H), 6.00 (s, 1H), 5.63 (s, 2H), 4.53-4.48 (m, 1H), 4.31-4.26 (m, 1H), 4.24-4.20 (m, 1H), 3.32 (s, 3H), 2.86-2.80 (m, 1H), 2.46 (s, 3H), 2.25-2.21 (m, 1H), 1.91-1.87 (m, 1H), 0.94-0.92 (m, 2H), 0.75-0.73 (m, 2H). LC-MS R_(T)=1.357 min, m/z=421.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.357 min, ESI+ found [M+H]=421.2.

Example 649 WX Method 133

4-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: 3,5-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

A mixture of 3,4-dihydro-2H-pyran (13.19 g, 156.85 mmol), 4-methylbenzenesulfonic acid (1.35 g, 7.84 mmol) and 3,5-dibromo-1H-1,2,4-triazole (10.0 g, 44.08 mmol) in tetrahydrofuran (50 mL) was heated at 25° C. for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (11 g, 80%) as a white solid, used as is in the next step as is.

Step 2: 3-bromo-N-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-5-amine

To a solution of 2,6-difluoroaniline (1.83 g, 14.15 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (1N in tetrahedron, 12.86 mL, 12.86 mmol), then 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (2.0 g, 6.43 mmol) at 0° C. The mixture was stirred at 0° C. for 15 h and quenched by addition of saturated ammonium chloride (10 mL). The resulting mixture was extracted with dichloromethane (2×20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to afford 5-bromo-N-(2,6-difluorophenyl)-2-tetrahydropyran-2-yl-1,2,4-triazol-3-amine (1.2 g, 52%) as a yellow solid, used in the next step as is.

Step 3: 3-bromo-N-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1,2,4-triazol-5-amine

To a solution of and 5-bromo-N-(2,6-difluorophenyl)-2-tetrahydropyran-2-yl-1,2,4-triazol-3-amine (700 mg, 1.95 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, 78 mg, 1.95 mmol). The reaction mixture was stirred at 50° C. for 0.5 h, then 2-(2-bromoethoxy)tetrahydro-2H-pyran (408 mg, 1.95 mmol) and sodium iodide (292 mg, 1.95 mmol) was added. The reaction mixture was stirred at 50° C. for 15 h and poured onto ice water (5 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 5-bromo-N-(2,6-difluorophenyl)-2-tetrahydropyran-2-yl-N-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-amine (800 mg, 84%) as yellow oil. LCMS R_(T)=0.893 min, m/z=508.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.893 min, ESI+ found M+H]=508.9.

Step 4: 2-((3-bromo-1H-1,2,4-triazol-5-yl)(2,6-difluorophenyl)amino)ethanol

A mixture of 5-bromo-N-(2,6-difluorophenyl)-2-tetrahydropyran-2-yl-N-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-amine (300 mg, 0.62 mmol) and 2,2,2-trifluoroacetic acid (70 mg, 0.62 mmol) in dichloromethane (10 mL) was stirred at 15° C. for 15 h and then concentrated under reduced pressure to afford crude 2-(N-(3-bromo-1H-1,2,4-triazol-5-yl)-2,6-difluoro-anilino)ethanol (160 mg, 81%) as a brown oil without other purification. LCMS R_(T)=0.551 min, m/z=318.9 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.551 min, ESI+ found [M+H]⁺=318.9.

Step 5: 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazol-5-amine

A mixture of 2-(N-(3-bromo-1H-1,2,4-triazol-5-yl)-2,6-difluoro-anilino)ethanol (160 mg, 0.50 mmol) and phosphoryl tribromide (144 mg, 0.50 mmol) in acetonitrile (5 mL) was heated at 50° C. for 15 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to afford 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 52%) as a brown oil. LCMS R_(T)=1.149 min, m/z=382.9 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 1.149 min, ESI+ found [M+H]=382.9.

Step 6: 2-bromo-4-(2,6-difluorophenyl)-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole

A mixture of 3-bromo-N-(2-bromoethyl)-N-(2,6-difluorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 15 hours. The reaction mixture was diluted with ice water (3 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford 2-bromo-4-(2,6-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole (65 mg, 83%) as a white solid. LCMS R_(T)=0.612 min, m/z=300.1 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.612 min, ESI+ found [M+H]=300.1.

Step 7: methyl 4-(2,6-difluorophenyl)-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of 2-bromo-4-(2,6-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole (60.0 mg, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (13 mg, 0.02 mmol) and triethylamine (0.27 mL, 1.99 mmol) in methanol (40 mL) was heated at 70° C. for 12 h under CO (40 psi) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford methyl 4-(2,6-difluorophenyl)-5,6-dihydroimidazo [1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 53%) as a yellow solid. LCMS R_(T)=0.566 min, m/z=280.8 [M+H]⁺, LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.566 min, ESI+ found [M+H]=280.8.

Step 8: 4-(2,6-difluorophenyl)-5,6-dihydro-4H-imidazo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of methyl 4-(2,6-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 0.11 mmol) and lithium hydroxide (13 mg, 0.54 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was stirred at 25° C. for 15 h. The reaction mixture was adjusted to pH=3 by addition of 1N HCl and concentrated under reduced pressure to afford crude methyl 4-(2,6-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxylate (30 mg, 100%) as a yellow solid. LCMS R_(T)=0.263 min, m/z=267.0 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.263 min, ESI+ found [M+H]=267.0.

Step 9: 4-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of 4-(2,6-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxylic acid (25 mg, 0.09 mmol), (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (17 mg, 0.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (40 mg, 0.21 mmol) and 1-hydroxybenzotriazole (28 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was added stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (35% to 65% acetonitrile/0.05% HCl in water acetonitrile) to afford 4-(2,6-difluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazole-2-carboxamide (6.5 mg, 18% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.52-7.43 (m, 1H), 7.21-7.17 (m, 2H), 6.46 (s, 1H), 4.72-4.60 (m, 3H), 4.60-4.53 (m, 2H), 4.51-4.45 (m, 1H), 4.43-4.35 (m, 1H), 3.38 (s, 3H), 2.91-2.82 (m, 1H), 2.45-2.35 (m, 4H). LCMS R_(T)=0.745 min, m/z=443.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.745 min, ESI+ found [M+H]=443.0

Example 650 WX Method 028

1-(2-pyridylmethyl)-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylate

A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (2.0 g, 15.7 mmol), potassium carbonate (4.35 g, 31.5 mmol) and 2-(bromomethyl)pyridine (2.71 g, 15.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylate (1.6 g, 47%) as a light-yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ8.85 (s, 1H), 8.52 (br. s, 1H), 7.83 (t, J=7.3 Hz, 1H), 7.38-7.31 (m, 2H), 5.62 (s, 2H), 3.82 (s, 3H).

Step 2: 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylate (500 mg, 2.29 mmol) and potassium hydroxide (0.26 g, 4.58 mmol) in ethanol (8 mL) and water (2 mL) was stirred for 2 h at 25° C. The solvent was removed under reduced pressure. The residue was dissolved in water (5 mL) and adjusted to pH=6 by addition of 2 N HCl and concentrated under reduced pressure to give crude 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylic acid (0.70 g, 149%) as a yellow solid, used as is in the next step.

Step 3: 1-(2-pyridylmethyl)-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a solution of 1-hydroxybenzotriazole (7.5 mg, 0.06 mmol) in N,N-dimethylformamide (2.5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (79 mg, 0.42 mmol), (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.28 mmol) and 1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxylic acid (56 mg, 0.28 mmol). The mixture was stirred at 20° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium hydroxide in water) to afford N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-(2-pyridylmethyl)-1,2,4-triazole-3-carboxamide (95.6 mg, 89.9%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ8.66 (s, 1H), 8.55 (d, J=4.4 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.42-7.38 (m, 2H), 6.32 (s, 1H), 5.62 (s, 2H), 4.55-4.42 (m, 2H), 4.31-4.29 (m, 1H), 3.38 (s, 3H), 2.91-2.81 (m, 1H), 2.36-2.28 (m, 1H). LCMS R_(T)=1.25 min, m/z=367.2 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.25 min, ESI+ found [M+H]=367.2

Example 651

1-(2-pyridylmethyl)-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 028. The crude was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to give 1-(2-pyridylmethyl)-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (64.3 mg, 63%) as a light-yellow semi-solid. ¹H NMR (400 MHz, CD₃OD) δ8.64 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 7.89-7.80 (m, 1H), 7.43-7.32 (m, 2H), 6.10 (s, 1H), 5.60 (s, 2H), 4.57-4.48 (m, 1H), 4.36-4.27 (m, 1H), 4.26-4.14 (m, 1H), 3.32 (s, 3H), 2.90-2.77 (m, 1H), 2.30-2.20 (m, 4H). LCMS R_(T)=0.652 min, m/z=381.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.652 min, ESI+ found [M+H]=381.2.

Example 652

1-(2-pyridylmethyl)-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 028. The crude was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to give 1-(2-pyridylmethyl)-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (70.3 mg, 75%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.65 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 7.87-7.84 (m, 1H), 7.40-7.37 (m, 2H), 6.00 (s, 1H), 5.60 (s, 2H), 4.56-4.51 (m, 1H), 4.30-4.28 (m, 1H), 4.23-4.18 (m, 1H), 3.32 (s, 3H), 2.88-2.81 (m, 1H), 2.29-2.24 (m, 1H), 1.93-1.90 (m, 1H), 0.96-0.93 (m, 2H), 0.76-0.74 (m, 2H). LCMS R_(T)=0.747 min, m/z=407.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2 mins) retention time 0.747 min, ESI+ found [M+H]=407.2.

Example 653

1-[(3-fluoro-2-pyridyl)methyl]-N-(6 S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 025. The crude was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to give 1-[(3-fluoro-2-pyridyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (16 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.65 (s, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.71-7.60 (m, 1H), 7.51 (s, 1H), 7.46-7.43 (m, 1H), 6.29 (s, 1H), 5.70 (s, 2H), 4.52-4.38 (m, 2H), 4.29-4.26 (m, 1H), 3.34 (s, 3H), 2.87-2.81 (m, 1H), 2.36-2.21 (m, 1H). LCMS R_(T)=1.05 min, m/z=385.1 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.05 min, ESI+ found [M+H]=385.1.

Example 654 WX Method 025

1-[(3-fluoro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: methyl 1-((3-fluoropyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (128 mg, 1.01 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1746 mg, 12.63 mmol) and 2-(bromomethyl)-3-fluoro-pyridine (240 mg, 1.26 mmol). The reaction mixture was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-[(3-fluoro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (120 mg, 40% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 2H), 7.42-7.38 (m, 1H), 7.28-7.26 (m, 1H), 5.58 (s, 2H), 3.91 (s, 3H).

Step 2: 1-((3-fluoropyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3-fluoro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (120 mg, 0.51 mmol) and lithium hydroxide (114 mg, 4.75 mmol) in tetrahydrofuran (8 mL) and water (4 mL) was stirred at 25° C. for 16 h. The mixture was adjusted to pH=6 by addition of 1N hydrochloric acid. The solid was collected by filtration and the dried to give crude 1-[(3-fluoro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (80 mg, 71%) as a white solid, used as is in the next step.

Step 3: 1-[(3-fluoro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a stirred solution of (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (26 mg, 0.14 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (27 mg, 0.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (38 mg, 0.20 mmol) and 1-[(3-fluoro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (30 mg, 0.14 mmol). The mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to afford 1-[(3-fluoro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (31 mg, 56%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.65 (s, 1H), 8.35 (d, J=4.8 Hz, 1H), 7.70-7.62 (m, 1H), 7.46-7.42 (m, 1H), 6.09 (s, 1H), 5.70 (s, 2H), 4.53-4.49 (m, 1H), 4.34-4.26 (m, 1H), 4.24-4.12 (m, 1H), 3.31 (s, 3H), 2.87-2.77 (m, 1H), 2.27-2.18 (m, 1H), 2.24 (s, 3H). LCMS R_(T)=1.17 min, m/z=399.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.17 min, ESI+ found [M+H]=399.2.

Example 655

1-[(3-fluoro-2-pyridyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 025. The crude was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to give 1-[(3-fluoro-2-pyridyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (38 mg, 65%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H), 8.35 (d, J=4.4 Hz, 1H), 7.69-7.60 (m, 1H), 7.45-7.43 (m, 1H), 5.99 (s, 1H), 5.70 (s, 2H), 4.52-4.47 (m, 1H), 4.33-4.24 (m, 1H), 4.23-4.12 (m, 1H), 3.29 (s, 3H), 2.85-2.78 (m, 1H), 2.28-2.17 (m, 1H), 1.94-1.85 (m, 1H), 0.97-0.88 (m, 2H), 0.75-0.69 (m, 2H). LCMS R_(T)=1.35 min, m/z=425.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.35 min, ESI+ found [M+H]=425.2.

Example 656

1-[(3-chloro-2-pyridyl)methyl]-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 022. The crude was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to give 1-[(3-chloro-2-pyridyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (44 mg, 73%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.62 (s, 1H), 8.43-8.41 (m, 1H), 7.91-7.89 (m, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.39-7.35 (m, 1H), 6.29 (d, J=1.8 Hz, 1H), 5.78 (s, 2H), 4.52-4.47 (m, 1H), 4.46-4.38 (m, 1H), 4.31-4.22 (m, 1H), 3.34 (s, 3H), 2.81-2.80 (m, 1H), 2.30-2.22 (m, 1H). LCMS R_(T)=1.21 min, m/z=401.1 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.21 min, ESI+ found [M+H]=401.1.

Example 657 WX Method 022

1-[(3-chloro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: 3-chloro-2-(chloromethyl)pyridine

To a stirred solution of (3-chloro-2-pyridyl)methanol (120 mg, 0.84 mmol) in dichloromethane (15 mL) was added thionylchloride (497 mg, 4.18 mmol) at 25° C. After addition, the mixture was stirred for 2 h and then quenched by addition of water (10 mL). The solution was adjusted to pH=11 by addition of saturated aqueous sodium bicarbonate and then extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude 3-chloro-2-(chloromethyl)pyridine (130 mg, 96%) as a yellow oil, used as is in the next step.

Step 2: methyl 1-((3-chloropyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (102 mg, 0.80 mmol) in N,N-dimethylformamide (5 mL) was added 3-chloro-2-(chloromethyl)pyridine (130 mg, 0.80 mmol) and potassium carbonate (333 mg, 2.41 mmol). The reaction mixture was stirred at 25° C. for 16 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-[(3-chloro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (125 mg, 62%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.38 (dd, J=1.4, 4.5 Hz, 1H), 8.26 (s, 1H), 7.68 (dd, J=1.3, 8.2 Hz, 1H), 7.22-7.18 (m, 1H), 5.65 (s, 2H), 3.92 (s, 3H).

Step 3: 1-((3-chloropyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1-[(3-chloro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (125 mg, 0.50 mmol) and lithium hydroxide (104 mg, 4.35 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred for 16 h at 25° C. The mixture was adjusted to pH=6 by addition of 1N HCl. The resulting solid was collected by filtration and dried under reduced pressure to give crude 1-[(3-chloro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (110 mg, 87%) as a white solid, used as is in the next step.

Step 4: 1-[(3-chloro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

To a stirred solution of 1-[(3-chloro-2-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (35 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (29 mg, 0.22 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (42 mg, 0.22 mmol) and (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (31 mg, 0.16 mmol). The mixture was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to give 1-[(3-chloro-2-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (45 mg, 72%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.62 (s, 1H), 8.43-8.41 (m, 1H), 7.91-7.89 (m, 1H), 7.39-7.35 (m, 1H), 6.09 (s, 1H), 5.78 (s, 2H), 4.54-4.50 (m, 1H), 4.35-4.27 (m, 1H), 4.25-4.14 (m, 1H), 3.31 (s, 3H), 2.88-2.78 (m, 1H), 2.29-2.18 (m, 1H), 2.24 (s, 3H). LCMS R_(T)=1.26 min, m/z=415.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.26 min, ESI+ found [M+H]=415.1.

Example 658

1-[(3-chloro-2-pyridyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 022. The crude was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to give 1-[(3-chloro-2-pyridyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (37 mg, 56%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.62 (s, 1H), 8.43-8.41 (m, 1H), 7.91-7.89 (m, 1H), 7.51 (s, 1H), 7.39-7.35 (m, 1H), 6.29 (s, 1H), 5.78 (s, 2H), 4.52-4.47 (m, 1H), 4.46-4.38 (m, 1H), 4.31-4.22 (m, 1H), 3.34 (s, 3H), 2.81-2.80 (m, 1H), 2.30-2.22 (m, 1H). LCMS R_(T)=1.44 min, m/z=441.1 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.44 min, ESI+ found [M+H]=441.1.

Example 659

1-[(2-fluorophenyl)methyl]-N-(7R)-2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1, 3]diazepin-7-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 091. The crude was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonia hydroxide in water) to afford N-(2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl)-1-[(2-fluorophenyl)methyl]-1,2,4-triazole-3-carboxamide (35 mg, 52% yield) as a white solid. The racemic material was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-(7R)-2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 3.433 min) (15.5 mg, 22%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.57 (s, 1H), 7.45-7.33 (m, 2H), 7.24-7.11 (m, 2H), 6.77 (s, 1H), 5.55 (s, 2H), 4.54-4.49 (m, 1H), 4.21-4.15 (m, 1H), 4.04-3.95 (m, 1H), 3.36 (s, 3H), 2.87-2.78 (m, 1H), 2.28-2.14 (m, 4H). LCMS RT=1.819 min; m/z=398.1 (M+H)⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.819 min, ESI+ found [M+H]=398.1

SFC conditions: Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: 40% of ethanol (0.05% DEA) in CO₂ Flow rate: 2.5 mL/min Column temp.: 35° C.

Example 660

1-[(2,6-difluorophenyl)methyl]-N-(7R)-2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 091. The crude was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonia hydroxide in water) to afford 1-[(2,6-difluorophenyl)methyl]-N-(2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]di azepin-7-yl)-1,2,4-triazole-3-carboxamide (35 mg, 50%) as a white solid. The racemic material was separated by chiral SFC to give: 1-[(2,6-difluorophenyl)methyl]-N-(7R)-2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.195 min) (18.7 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.60 (s, 1H), 7.50-7.42 (m, 1H), 7.07-7.03 (m, 2H), 6.77 (s, 1H), 5.60 (s, 2H), 4.53-4.48 (m, 1H), 4.21-4.15 (m, 1H), 4.03-3.95 (m, 1H), 3.36 (s, 3H), 2.84-2.76 (m, 1H), 2.26-2.16 (m, 4H). LCMS RT=1.817 min; m/z=416.2 (M+H)⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.817 min, ESI+ found [M+H]=416.2.

SFC conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 umMobile phase: A: CO₂ B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 minFlow rate: 2.8 mL/min Column temperature:40° C.

Example 661

1-[(2,5-difluorophenyl)methyl]-N-(7R)-2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 091. The crude was purified by RP-HPLC (20% to 50% acetonitrile/0.05% ammonia hydroxide in water) to afford 1-[(2,5-difluorophenyl)methyl]-N-(2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]di azepin-7-yl)-1,2,4-triazole-3-carboxamide (50 mg, 71%) as a white solid. The racemic mixture was separated by chiral SFC to give:

1-[(2,5-difluorophenyl)methyl]-N-(7R)-2,9-dimethyl-8-oxo-6,7-dihydro-5H-imidazo[1,2-a][1,3]diazepin-7-yl-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.786 min) (21.5 mg, 47%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.61 (s, 1H), 7.22-7.11 (m, 3H), 6.78 (s, 1H), 5.54 (s, 2H), 4.55-4.48 (m, 1H), 4.21-4.16 (m, 1H), 4.05-3.98 (m, 1H), 3.36 (s, 3H), 2.86-2.76 (m, 1H), 2.31-2.15 (m, 4H). LCMS R_(T)=1.852 min; m/z=416.1 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 1.852 min, ESI+ found [M+H]=416.1

SFC conditions: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 umMobile phase: A: CO₂ B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 minFlow rate: 2.8 mL/min Column temperature:40° C.

Example 662 WX Method 082

1-benzyl-N-(6S)-4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-(6R)-4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: N-(5-bromo-1H-pyrazol-3-yl)formamide

The solution of compound 5-bromo-1H-pyrazol-3-amine (500 g, 3.1 mol) in formic acid (1.5 L) was refluxed at 110° C. for 3 hr. TLC (dichloromethane: methanol=10:1, R_(f)=0.35) showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and the residue was washed with 2-methoxy-2-methylpropane (1 L) two times to afford N-(5-bromo-1H-pyrazol-3-yl)formamide (538 g, 92% yield) as a white solid, used as is in the next step.

Step 2: 5-bromo-N-methyl-1H-pyrazol-3-amine

With two reactions carried out in parallel, to the solution of lithium aluminum hydride (105 g, 2.8 mol) in tetrahydrofuran (2.6 L) was added compound N-(5-bromo-1H-pyrazol-3-yl)formamide (265 g, 1.4 mol) at 0° C. and the reaction mixture was stirred at 10° C. for 16 hr. Two reactions were combined and the reaction mixture was quenched with water (106 mL) and 15% NaOH solution (106 mL). The resulting solid was filtered and washed with tetrahydrofuran (2×2 L). The filtrate was concentrated under reduced pressure and the crude product was purified by silica column chromatography (petroleum ether:ethyl acetate=50:1-3:1) to afford 5-bromo-N-methyl-1H-pyrazol-3-amine (200 g, 41% yield) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 4.85 (s, 2H), 2.70-2.79 (m, 3H).

Step 3: N-(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide

The solution of compound 5-bromo-N-methyl-1H-pyrazol-3-amine (175 g, 1.0 mol) and compound 4-chlorobutanoyl chloride (661 g, 4.7 mol) was stirred at 60° C. for 1 hr. The reaction mixture was quenched with methanol (800 mL) at −30° C. and allowed to warm to 0° C. and stirred for 1 h. Then the mixture was neutralized with aq. NaOH (10M) to pH 6, the mixture was concentrated, extracted with dichloromethane (3×300 mL) and the combined filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=1:0˜30:1) to afford N-(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide (180 g, 64% yield) as a yellow oil, used as is in the next step.

Step 4: 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

With two reactions carried out in parallel a solution of compound N-(3-bromo-1H-pyrazol-5-yl)-4-chloro-N-methylbutanamide (100 g, 356 mmol) in acetonitrile (1 L) was added cesium carbonate (232 g, 713 mmol) and stirred at 30° C. for 16 hr. The two reactions were combined for workup, filtered the Cs₂CO₃ and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate=50:1-1:1) to afford 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (110 g, 63% yield) as a yellow oil, used as is in the next step.

Step 5: 2-bromo-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)

To the solution of compound 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (100 g, 410 mmol) in dichloromethane (2 L) was added N,N,N′,N′-tetramethylethane-1,2-diamine (143 g, 1.23 mol), stirred at −15° C. for 0.5 hr, followed addition of iodo(trimethyl)silane (246 g, 1.23 mol) drop wise at −15° C. for 1.5 hr. Subsequently iodine (312 g, 1.23 mol) was added and the reaction mixture was stirred at −15° C. 3 hr. The reaction mixture was quenched with aq. Na₂SO₃ (10M, 1 L), filtered, washed with brine (1 L), extracted with dichloromethane (2×3 L), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford compound 2-bromo-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (170 g, crude) as a brown solid, which was used in next step without further purification.

Step 6: 6-azido-2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

The solution of compound 2-bromo-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (170 g, 460 mmol) in dimethylformamide (500 mL) was added sodium azide (45 g, 670 mol) and stirred at 30° C. for 2 hr. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (2×2 L), the combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford 6-azido-2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (100 g, crude) as a yellow oil, which was used in next step without further purification.

Step 7: 6-amino-2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

The solution of compound 6-azido-2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (100 g, 350 mmol) in methanol (1 L) was added Pd/C (15 g), the mixture was stirred at 30° C. for 16 hr under H₂ (30 psi). Pd/C was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica column (petroleum ether: ethyl acetate=50:1-0:1) to afford 6-amino-2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (50 g, yield: 54%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 6.43 (s, 1H), 4.17-4.27 (m, 1H), 4.05 (ddd, J=14.6, 12.7, 6.7 Hz, 1H), 3.19 (s, 3H), 3.13-3.17 (m, 1H), 2.44-2.50 (m, 1H), 1.73-1.83 (m, 1H).

Step 8: 1-benzyl-N-(2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2-bromo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (4.0 g, 15.44 mmol), 1-hydroxybenzotriazole (3.1 g, 23.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (4.4 g, 23.16 mmol) and 1-benzyl-1,2,4-triazole-3-carboxylic acid (3.8 g, 18.53 mmol) in N,N-dimethylformamide (20 mL) was stirred at 20° C. for 16 h. The reaction mixture was poured into water (100 mL) and stirred for 20 min. The resulting solid was collected by filtration and dried to give 1-benzyl-N-(2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (6.8 g, 99% yield) as white solids, used as is in the next step.

Step 9: 1-benzyl-N-[4-methyl-5-oxo-2-(3-oxopropyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and (E)-1-benzyl-N-(2-(3-hydroxyprop-1-en-1-yl)-4-methyl-5-oxo-5,6,7,8]tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide (300 mg, 0.68 mmol), N,N-di isopropylethylamine (262 mg, 2.03 mmol), allyl alcohol (118 mg, 2.03 mmol) and bis(tri-tert-butylphosphine)palladium (34 mg, 0.07 mmol) in 1,4-dioxane (10 mL) was stirred at 80° C. for 12 h under N₂ atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give a mixture of 1-benzyl-N-[4-methyl-5-oxo-2-(3-oxopropyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and (E)-1-benzyl-N-(2-(3-hydroxyprop-1-en-1-yl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol o[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (250 mg, 88%, 3:7 ratio) as a yellow solid, used as is in the next step.

Step 10: [(E)-3-[6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]allyl]methanesulfonate

To a solution of (E)-1-benzyl-N-(2-(3-hydroxyprop-1-en-1-yl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 0.09 mmol) in dichloromethane (5 mL) was added triethylamine (38 mg, 0.30 mmol) and methanesulfonyl chloride (16 mg, 0.14 mmol). The reaction mixture was stirred at 15° C. for 12 h. The mixture was washed with brine (5 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure to give crude [(E)-3-[6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]allyl]methanesulfonate (35 mg, 74%) as a yellow oil, used as is in the next step.

Step 11: 1-benzyl-N-[4-methyl-2-[(E)-3-morpholinoprop-1-enyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

To a solution of [(E)-3-[6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]allyl]methanesulfonate (35 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (48 mg, 0.35 mmol) and morpholine (18 mg, 0.21 mmol). The reaction mixture was stirred at 35° C. for 1 h and then poured into water (15 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried with sodium sulfate and concentrated under reduced pressure to give crude 1-benzyl-N-[4-methyl-2-[(E)-3-morpholinoprop-1-enyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (30 mg, 87%) as a yellow oil, used as is in the next step.

Step 12: 1-benzyl-N-(6S)-4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-(6R)-4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-N-[4-methyl-2-[(E)-3-morpholinoprop-1-enyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (30 mg, 0.06 mmol) and Pd/C (10%, 19 mg, 0.02 mmol) in ethyl acetate (10 mL) was hydrogenated (15 psi) for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC ((acetonitrile 20-50%/0.05% NH₃.H₂O in water)) to give 1-benzyl-N-[4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1,2,4-triazole-3-carboxamide (15 mg, 50%) as a white solid.

Two batches of the racemic material (40 mg) were separated by chiral SFC to give:

1-benzyl-N-(6S)-4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, Retention time=4.402 min) (18.3 mg, 44%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.57 (s, 1H), 7.38-7.32 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.54-4.49 (m, 1H), 4.33-4.30 (m, 1H), 4.27-4.23 (m, 1H), 3.72 (t, J=4.4 Hz, 4H), 3.32 (s, 3H), 2.83-2.80 (m, 1H), 2.66-2.48 (m, 8H), 2.26-2.24 (m, 1H), 1.92-1.88 (m, 2H). LC-MS R_(T)=1.449 min, m/z=493.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.449 min, ESI+ found [M+H]=493.3.

1-benzyl-N-(6R)-4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, Retention time=4.483 min) (18.8 mg, 45%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.56 (s, 1H), 7.38-7.32 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.54-4.49 (m, 1H), 4.33-4.30 (m, 1H), 4.27-4.21 (m, 1H), 3.69 (t, J=4.8 Hz, 4H), 3.33 (s, 3H), 2.83-2.80 (m, 1H), 2.66-2.62 (m, 2H), 2.48-2.40 (m, 6H), 2.26-2.24 (m, 1H), 1.89-1.86 (m, 2H). LC-MS R_(T)=1.449 min, m/z=493.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.449 min, ESI+ found [M+H]=493.3.

SFC condition: column: chiralpak AD-3 (100×4.6 mm), 3 um mobile phase: A:CO2; B: MeOH (0.05% DEA) gradient: from 5 to 40 of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example 663 WX Method 031

1-[(2-methyl-3-pyridyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Step 1: 1-[(2-methyl-3-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid

A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (239 mg, 1.88 mmol), potassium carbonate (520 mg, 3.76 mmol) and 3-(bromomethyl)-2-methyl-pyridine (350 mg, 1.88 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h and filtered. The filtrate was concentrated under reduced pressure to afford crude methyl 1-[(2-methyl-3-pyridyl)methyl]-1,2,4-triazole-3-carboxylate (0.30 g, 69%) as a yellow oil. The above crude was diluted with water (5 mL) and stirred for 10 min at 25° C. The mixture was adjusted to pH=6 by addition of 2N HCl. The resulting mixture was concentrated under reduced pressure to give crude 1-[(2-methyl-3-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (260 mg, 92%) as yellow solid, used as is in the next step.

Step 2: 1-[(2-methyl-3-pyridyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (79 mg, 0.41 mmol), (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (49 mg, 0.27 mmol), 1-hydroxybenzotriazole (7 mg, 0.05 mmol) and 1-[(2-methyl-3-pyridyl)methyl]-1,2,4-triazole-3-carboxylic acid (60 mg, 0.27 mmol) in N,N-dimethylformamide (2.5 mL) was stirred at 20° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 17-47/0.05% ammonium hydroxide in water to afford 1-[(2-methyl-3-pyridyl)methyl]-N-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (36.1 mg, 34%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.63 (s, 1H), 8.41 (d, J=4.4 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.56-7.52 (m, 1H), 7.32-7.29 (m, 1H), 6.33-6.31 (m, 1H), 5.60 (s, 2H), 4.55-4.42 (m, 2H), 4.35-4.24 (m, 1H), 3.37 (s, 3H), 2.95-2.82 (m, 1H), 2.61 (s, 3H), 2.35-2.25 (m, 1H). LCMS R_(T)=1.068 min, m/z=381.2 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.068 min, ESI+ found [M+H]=381.2.

Example 664

1-[(2-methyl-3-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 031. The crude was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to give 1-[(2-methyl-3-pyridyl)methyl]-N-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (28.6 mg, 26%) as a light-yellow semi-solid.

¹H NMR (400 MHz, CD₃OD) δ8.61 (s, 1H), 8.39 (d, J=4.8 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.30-7.27 (m, 1H), 6.11 (s, 1H), 5.58 (s, 2H), 4.55-4.50 (m, 1H), 4.35-4.27 (m, 1H), 4.26-4.16 (m, 1H), 3.32 (s, 3H), 2.90-2.78 (m, 1H), 2.59 (s, 3H), 2.30-2.20 (m, 4H). LCMS R_(T)=1.165 min, m/z=395.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.165 min, ESI+ found [M+H]=395.2.

Example 665

1-[(2-methyl-3-pyridyl)methyl]-N-(6S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 031. The crude was purified by RP-HPLC (acetonitrile 17-47%/0.05% ammonium hydroxide in water) to give 1-[(2-methyl-3-pyridyl)methyl]-N-(6 S)-2-cyclopropyl-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl-1,2,4-triazole-3-carboxamide (37 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.62 (s, 1H), 8.40 (d, J=4.0 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.31-7.28 (m, 1H), 6.01 (s, 1H), 5.59 (s, 2H), 4.55-4.50 (m, 1H), 4.35-4.27 (m, 1H), 4.25-4.15 (m, 1H), 3.33-3.32 (m, 3H), 2.90-2.78 (m, 1H), 2.60 (s, 3H), 2.33-2.19 (m, 1H), 1.96-1.87 (m, 1H), 0.98-0.91 (m, 2H), 0.78-0.70 (m, 2H). LCMS R_(T)=1.287 min, m/z=421.3 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3 mins) retention time 1.287 min, ESI+ found [M+H]=421.3.

Examples 666 and 667 WX Method 127

(5R)-5-(2-fluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazol-[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (5S)-5-(2-fluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Step 1: methyl 4-(4-bromo-2-fluorophenyl)-4-oxobutanoate

To a solution of 1-bromo-3-fluorobenzene (5.0 g, 28.57 mmol) in 1,2-dichloroethane (100 mL) was added aluminumchloride (15.2 g, 114.29 mmol) and methyl 4-chloro-4-oxobutyrate (8.6 g, 57.14 mmol). The mixture was heated at 70° C. for 12 h and cooled. The reaction was slowly quenched by addition of water (20 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford methyl 4-(4-bromo-2-fluoro-phenyl)-4-oxo-butanoate (2.0 g, 24%) as a yellow solid. LCMS R_(T)=0.995 min, m/z=291.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.995 min, ESI+ found [M+H]=291.1

Step 2: tert-butyl (2-(4-bromo-2-fluorophenyl)-5-oxopyrrolidin-1-yl)carbamate

To a solution of methyl 4-(4-bromo-2-fluoro-phenyl)-4-oxo-butanoate (2.0 g, 6.91 mmol) in tetrahydrofuran (10 mL) and acetic acid (5 mL) was added tert-butyl hydrazinecarboxylate (1.3 g, 10.38 mmol). The mixture was stirred at 40° C. for 12 h and then sodiumcyanoborohydride (652 mg, 10.38 mmol) was added. Stirring was continued for another 6 h and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford tert-butyl N-[2-(2-fluorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (800 mg, 78%) as yellow oil. LCMS R_(T)=1.067 min, m/z=319.0 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 1.067 min, ESI+ found [M−55]=319.0

Step 3: tert-butyl (2-(2-fluorophenyl)-5-oxopyrrolidin-1-yl)carbamate

A mixture of tert-butyl N-[2-(4-bromo-2-fluoro-phenyl)-5-oxo-pyrrolidin-1-yl]carbamate (800 mg, 2.14 mmol) and Pd/C (10%, 228 mg, 0.21 mmol) in methanol (10 mL) was hydrogenated (15 psi) at 25° C. for 4 h and then filtered. The filtrate was concentrated under reduced pressure to afford crude tert-butyl N-[2-(2-fluorophenyl)-5-oxo-pyrrolidin-1-yl]carbamate (500 mg, 79%) as a white solid.

LCMS R_(T)=0.972 min, m/z=239.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0 mins) retention time 0.972 min, ESI+ found [M−55]=239.1

Step 4: 1-amino-5-(2-fluorophenyl)pyrrolidin-2-one hydrochloride

A solution of tert-butyl (2-(2-fluorophenyl)-5-oxopyrrolidin-1-yl)carbamate (400 mg, 1.36 mmol) in ethyl acetate (5 mL) was added HCl (4N in ethyl acetate, 1.0 mL, 4.0 mmol). The mixture was stirred at 25° C. for 4 h and then concentrated under reduced pressure to afford crude 1-amino-5-(2-fluorophenyl)pyrrolidin-2-one hydrochloride (400 mg, 100%) as white solid, used as is in the next step.

Step 5: (Z)-ethyl 2-amino-2-((2-(2-fluorophenyl)-5-oxopyrrolidin-1-yl)imino)acetate

To a solution of 1-amino-5-(2-fluorophenyl)pyrrolidin-2-one hydrochloride (400 mg, 2.06 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino-acetate (1.8 g, 12.36 mmol). The mixture was stirred at 40° C. for 12 h and concentrated under reduced pressure to afford crude ethyl (2Z)-2-amino-2-[2-(2-fluorophenyl)-5-oxo-pyrrolidin-1-yl]imino-acetate (500 mg, 82%) as a yellow oil, used as is in the next step.

Step 6: methyl 7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate

A solution of ethyl (2Z)-2-amino-2-[2-(2-fluorophenyl)-5-oxo-pyrrolidin-1-yl]imino-acetate (500 mg, 1.7 mmol) in phosphorus oxychloride (5.0 mL, 135.9 mmol) was heated at 120° C. for 1 h. After cooled, the mixture was slowly quenched by addition of water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with 20% sodium bicarbonate (20 mL), brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% ethyl acetate in petroleum ether) to afford ethyl 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (400 mg, 85%) as a light yellow oil. LCMS R_(T)=0.760 min, m/z=275.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.760 min, ESI+ found [M+H]=275.9

Step 7: 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of ethyl 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (400 mg, 1.45 mmol) and potassium hydroxide in ethanol (20 mL) and water (5 mL) was stirred at 25° C. for 12 h. The ethanol was removed under reduced pressure. The residue was diluted with water (20 mL) and adjusted to pH=4 by addition of 2N HCl. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated under reduced pressure to afford crude 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (200 mg, 55%) as a yellow solid, used as is in the next step.

Step 8: (5R)-5-(2-fluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (5S)-5-(2-fluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture of (6S)-6-amino-2,4-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (40 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol), 1-hydroxybenzotriazole (31 mg, 0.21 mmol). and 5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid (50 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (0-2% methanol in dichloromethane, R_(f)=0.5) to afford N—((S)-2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (60 mg, 69%) as a white solid. The racemic material was separated by chiral SFC to give:

(5R)-5-(2-fluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 1, retention time 2.561 min) (25 mg, 41.7%) as white solids. ¹H NMR (400 MHz, CD₃OD) δ7.45-7.38 (m, 1H), 7.24-7.14 (m, 3H), 6.12 (s, 1H), 5.79-5.75 (m, 1H), 4.53-4.49 (m, 1H), 4.35-4.28 (m, 1H), 4.26-4.16 (m, 1H), 3.37-3.33 (m, 3H), 3.32-3.27 (m, 1H), 3.19-3.05 (m, 2H), 2.88-2.79 (m, 1H), 2.78-2.68 (m, 1H), 2.26 (s, 3H), 2.25-2.17 (m, 1H). LCMS R_(T)=0.91 min, m/z=424.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.1% trifluoacetic acid over 2.0 mins) retention time 0.91 min, ESI+ found [M+H]=424.2.

(5S)-5-(2-fluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 2, retention time 2.779 min) (25 mg, 41.7%) white solids. ¹H NMR (400 MHz, CD₃OD) δ7.45-7.38 (m, 1H), 7.24-7.14 (m, 3H), 6.12 (s, 1H), 5.80-5.76 (m, 1H), 4.54-4.49 (m, 1H), 4.35-4.28 (m, 1H), 4.26-4.16 (m, 1H), 3.37-3.33 (m, 3H), 3.32-3.27 (m, 1H), 3.19-3.05 (m, 2H), 2.88-2.79 (m, 1H), 2.78-2.68 (m, 1H), 2.26 (s, 3H), 2.25-2.17 (m, 1H). LCMS R_(T)=0.92 min, m/z=424.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.1% trifluoacetic acid over 2.0 mins) retention time 0.92 min, ESI+ found [M+H]=424.2.

SFC conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min, Column temp.: 40° C.

Examples 668 and 669

(5R)-5-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (5S)-5-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 127. The crude was purified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide in water) to afford 5-(2-fluorophenyl)-N—((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (60 mg, 66%). The racemic material was separated by chiral SFC to give:

(5R)-5-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 1, retention time 2.784 min) (25 mg, 41.2%)¹H NMR (400 MHz, CD3OD) δ 7.51 (d, J=2.0 Hz, 1H), 7.43-7.37 (m, 1H), 7.22-7.13 (m, 3H), 6.29 (d, J=2.0 Hz, 1H), 5.77 (dd, J=8.0, 12.0 Hz, 1H), 4.52-4.38 (m, 2H), 4.30-4.22 (m, 1H), 3.34 (s, 3H), 3.30-3.25 (m, 1H), 3.19-3.03 (m, 2H), 2.88-2.80 (m, 1H), 2.74-2.68 (m, 1H), 2.30-2.21 (m, 1H). LCMS R_(T)=0.76 min, m/z=410.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.76 min, ESI+ found [M+H]=410.0.

(5S)-5-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (Peak 2, retention time 2.950 min) (24 mg, 39.6%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.52 (s, 1H), 7.43-7.37 (m, 1H), 7.22-7.12 (m, 3H), 6.30 (s, 1H), 5.80-5.76 (m, 1H), 4.53-4.38 (m, 2H), 4.30-4.22 (m, 1H), 3.35 (s, 3H), 3.30-3.25 (m, 1H), 3.19-3.03 (m, 2H), 2.90-2.79 (m, 1H), 2.76-2.67 (m, 1H), 2.30-2.21 (m, 1H). LCMS R_(T)=0.75 min, m/z=410.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.1% trifluoacetic acid over 1.5 mins) retention time 0.75 min, ESI+ found [M+H]=410.0.

SFC conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min Flow rate: 2.8 mL/min, Column temp.: 40° C.

Examples 670-697 (“Chiral Table 1”)

In each example below, Solvent A is CO₂ and Solvent B is 0.1% NH₄OH/Methanol. Column temperature is 40° C. in each example.

Initial Final column Ex # Instrument % B % B Wavelength column type dimension flow rate 670 PIC 100 30 220 Chiralpak 150 × 21.2 mm 70 Chiral AD 671 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 672 PIC 100 30 220 Whelko-01 150 × 21.2 mm 70 Chiral 673 PIC 100 20 220 Chiralpak 150 × 21.2 mm 70 Chiral AS 674 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 675 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 676 PIC 100 30 220 Chiralpak 150 × 21.2 mm 70 Chiral AD 677 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 678 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 679 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 680 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 681 Thar 100 220 Cellulose-1 150 × 30 mm 100 Chiral 682 Jasco 30 30 240 Chiralpak 250 × 21.2 mm, 70 150 nm OX 5 um 683 Jasco 35 35 240 Chiralpak 250 × 21.2 mm, 70 150 nm OX 5 um 684 Jasco 35 35 240 Chiralpak 250 × 21.2 mm, 70 150 nm OX 5 um 685 Jasco 30 30 240 Chiralpak 250 × 21.2 mm, 70 150 nm OX 5 um 686 PIC 100 35 35 230 Whelko-01 150 × 21.2 mm 70 Chiral 687 PIC 100 20 20 230 Cellulose-1 150 × 21.2 mm 70 Chiral 688 PIC 100 20 20 230 Chiralpak 150 × 21.2 mm 70 Chiral AD 689 PIC 100 35 35 230 Whelko-01 150 × 21.2 mm 70 Chiral 690 PIC 100 20 20 230 Cellulose-1 150 × 21.2 mm 70 Chiral 691 PIC 100 20 20 230 Chiralpak 150 × 21.2 mm 70 Chiral AD 692 PIC 100 254 Chiralpak 150 × 21.2 mm 70 Chiral nm AS 693 PIC 100 254 Cellulose-3 150 × 21.2 mm 70 Chiral nm 694 PIC 100 254 Chiralpak 150 × 21.2 mm 70 Chiral nm AD 695 Thar 100 254 Chiralpak 150 × 30 mm 100 Chiral nm AD 696 PIC 100 254 Chiralpak 150 × 21.2 mm 70 Chiral nm AS 697 PIC 100 254 Chiralpak 150 × 21.2 mm 70 Chiral nm AD

Example 698 Suzuki Method 1

1-benzyl-N-[2-(1-ethylpyrazol-4-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

To a microwave vial was charged 1-benzyl-N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide (100 mg, 0.2251 mmol), 1-ethyl-4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, (61.21 mg, 0.27 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (17.34 mg, 0.023 mmol). The solids were dissolved in a mixture of acetonitrile (0.6431 mL) and 1N potassium carbonate (0.6431 mL, 0.6431 mmol), the vial was sealed and irradiated in a microwave at 110° C. for 10 min. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (2×5 mL), brine and dried over sodium sulphate. The filtrate was concentrated to dryness in vacuo and the residue was purified by reverse phase HPLC to afford 1-benzyl-N-[2-(1-ethylpyrazol-4-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide as a white solid (30 mg, 29% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 8.04 (d, J=0.7 Hz, 1H), 7.72 (d, J=0.7 Hz, 1H), 7.55-7.21 (m, 5H), 6.50 (s, 1H), 5.48 (s, 2H), 4.45-4.28 (m, 2H), 4.24-4.09 (m, 3H), 3.26 (s, 3H), 2.69-2.57 (m, 1H), 2.43-2.30 (m, 1H), 1.39 (t, J=7.3 Hz, 3H). LC-MS R_(T)=4.04 min, m/z=460.2 [M+H]⁺. LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.04 min, ESI+ found [M+H]=460.2.

SFC condition: Column: Cellulose-1 150×21.2 mm, 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH), Isocratic Gradient: 40% B for 37.5 min. Flow rate: 70 mL/min Column temperature: 40° C., BPR: 120 bar.

Example 699

1-benzyl-N-[2-(1-isobutylpyrazol-4-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide Suzuki Method 1. (20 mg, 41% Yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.54 (d, J=7.7 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.73 (d, J=0.7 Hz, 1H), 7.44-7.23 (m, 5H), 6.51 (s, 1H), 5.48 (s, 2H), 4.46-4.29 (m, 2H), 4.25-4.11 (m, 1H), 3.93 (d, J=7.2 Hz, 2H), 3.26 (s, 3H), 2.71-2.58 (m, 1H), 2.43-2.32 (m, 1H), 2.19-2.05 (m, 1H), 0.85 (d, J=6.7 Hz, 6H). LC-MS R_(T)=4.51 min, m/z=488.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.51 min, ESI+ found [M+H]=488.2.

Example 700

5-bromo-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]isoquinoline-3-carboxamide

Method B. (74 mg, 90% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (d, J=0.8 Hz, 1H), 9.13 (d, J=7.7 Hz, 1H), 8.58 (t, J=0.9 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.26 (dd, J=7.5, 1.0 Hz, 1H), 7.77 (dd, J=8.2, 7.5 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H), 4.50-4.37 (m, 2H), 4.33-4.19 (m, 1H), 3.29 (s, 3H), 2.81-2.71 (m, 1H), 2.46-2.35 (m, 1H). LC-MS R_(T)=5.10 min, m/z=414.0 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.10 min, ESI+ found [M+H]=414.0.

Example 701

5-bromo-N-[rac-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]isoquinoline-3-carboxamide

Method B. (74 mg, 88% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (d, J=0.9 Hz, 1H), 9.11 (d, J=7.8 Hz, 1H), 8.58 (t, J=0.9 Hz, 1H), 8.40-8.31 (m, 1H), 8.26 (dd, J=7.5, 1.0 Hz, 1H), 7.77 (dd, J=8.2, 7.5 Hz, 1H), 6.15 (s, 1H), 4.54-4.38 (m, 1H), 4.38-4.25 (m, 1H), 4.24-4.08 (m, 1H), 3.26 (s, 3H), 2.89 (d, J=0.4 Hz, 1H), 2.80-2.66 (m, 2H), 2.42-2.31 (m, 1H), 2.19 (d, J=0.5 Hz, 3H). LC-MS R_(T)=5.32 min, m/z=428.0 [M+H]⁺. LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.32 min, ESI+ found [M+H]=428.0.

Example 702

5-phenyl-N-[rac-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]isoquinoline-3-carboxamide Method B and Subsequently Suzuki Method 1. (32 mg, 36% Yield)

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (d, J=0.9 Hz, 1H), 9.06 (d, J=7.7 Hz, 1H), 8.44-8.18 (m, 2H), 7.97-7.79 (m, 2H), 7.66-7.46 (m, 5H), 6.12 (s, 1H), 4.45-4.34 (m, 1H), 4.34-4.22 (m, 1H), 4.22-4.08 (m, 1H), 3.24 (s, 3H), 2.75-2.62 (m, 1H), 2.39-2.27 (m, 1H), 2.17 (s, 3H). LC-MS R_(T)=7.20 min, m/z=426.1 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 7.20 min, ESI+ found [M+H]=426.1.

Example 703

5-phenyl-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]isoquinoline-3-carboxamide Method B and Subsequently Suzuki Method 1. (18 mg, 21% Yield)

¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (d, J=0.9 Hz, 1H), 9.08 (d, J=7.7 Hz, 1H), 8.40-8.25 (m, 2H), 7.97-7.79 (m, 2H), 7.66-7.46 (m, 6H), 6.33 (d, J=2.0 Hz, 1H), 4.45-4.32 (m, 2H), 4.32-4.17 (m, 1H), 3.27 (s, 3H), 2.78-2.64 (m, 1H), 2.44-2.31 (m, 1H). LC-MS R_(T)=6.97 min, m/z=412.1 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 6.97 min, ESI+ found [M+H]=412.1.

Example 704

1-benzyl-N-[2-(1-ethylpyrazol-3-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide Suzuki Method 1 (38 mg, 61% Yield)

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.46-7.25 (m, 5H), 6.59 (s, 1H), 6.50 (d, J=2.2 Hz, 1H), 5.48 (s, 2H), 4.44-4.33 (m, 2H), 4.28-4.19 (m, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.28 (s, 3H), 2.69-2.60 (m, 1H), 2.42-2.33 (m, 1H), 1.39 (t, J=7.3 Hz, 3H). LC-MS R_(T)=5.45 min, m/z=460.2 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.45 min, ESI+ found [M+H]=460.2.

Example 705 Method GH5

1-benzyl-N-[4-methyl-1-oxo-1-(pyrazol-1-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: 1-benzyl-N-(2-(hydroxymethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (678 mg, 1.725 mmol, 1.0 equiv) in methanol (15 mL) cooled to 0° C. was added sodium borohydride (131 mg, 3.45 mmol, 2.0 equiv). The reaction mixture was warmed to RT and stirred 2 h. The reaction was quenched with 5% aqueous citric acid (50 mL) and extracted with dichloromethane (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 15% methanol in dichloromethane) affording 1-benzyl-N-[2-(hydroxymethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (350 mg, 51% yield). LCMS R_(T)=0.97 min [2 min method], m/z=396 [M+H]⁺.

Step 2: (6-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)methyl methanesulfonate

To a solution of 1-benzyl-N-[2-(hydroxymethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (350 mg, 0.885 mmol, 1.0 equiv) in dichloromethane (10 mL) cooled to 0° C. was added triethylamine (0.370 mL, 2.66 mmol, 3.0 equiv) and methanesulfonyl chloride (0.137 mL, 1.77 mmol, 2.0 equiv). The reaction mixture was allowed to warm slowly to RT over 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (3×50 mL). The combined organics were washed with water and brine, dried over sodium sulfate and concentrated to dryness in vacuo affording (6-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)methyl methanesulfonate (405 mg, 97% yield) which was used without further purification. LCMS R_(T)=1.13 min [2 min method], m/z=474 [M+H]⁺.

Step 3: 1-benzyl-N-[4-methyl-5-oxo-2-(pyrazol-1-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

To a solution of (6-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)methyl methanesulfonate (60 mg, 0.126 mmol, 1.0 equiv) in acetonitrile (1 mL) was added pyrazole (17 mg, 0.252 mmol, 2.0 equiv) and cesium carbonate (82 mg, 0.252 mmol, 2.0 equiv). The resulting mixture was stirred for 16 hr at RT. The mixture was then filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording 1-benzyl-N-[4-methyl-5-oxo-2-(pyrazol-1-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (31 mg, 55% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.53 (d, J=7.8 Hz, 1H), 7.78 (dd, J=2.3, 0.7 Hz, 1H), 7.44 (dd, J=1.9, 0.7 Hz, 1H), 7.41-7.27 (m, 5H), 6.25 (dd, J=2.3, 1.8 Hz, 1H), 6.21 (s, 1H), 5.48 (s, 2H), 5.32-5.20 (m, 2H), 4.38-4.25 (m, 2H), 4.16 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 3.20 (s, 3H), 2.65-2.53 (m, 1H), 2.42-2.30 (m, 1H). LCMS R_(T)=3.70 min [10 min method], m/z=446.2 [M+H]⁺.

Example 706

1-benzyl-N-[4-methyl-2-[(2-methylimidazol-1-yl)methyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

The title compound was prepared from 2-methylimidazole according to Method GH5. Yield of final step: 37 mg, 64%, obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.53 (d, J=7.8 Hz, 1H), 7.44-7.25 (m, 5H), 7.08 (d, J=1.3 Hz, 1H), 6.71 (d, J=1.3 Hz, 1H), 6.23 (s, 1H), 5.48 (s, 2H), 5.12-4.96 (m, 2H), 4.39-4.23 (m, 2H), 4.16 (ddd, J=14.5, 12.6, 6.6 Hz, 1H), 3.20 (s, 3H), 2.68-2.52 (m, 1H), 2.44-2.34 (m, 1H), 2.31 (s, 3H).

LCMS RT=2.66 min [10 min method], m/z=460.2 [M+H]⁺.

Example 707

(S)-1-benzyl-N-[2-(imidazol-1-ylmethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

The title compound was prepared from imidazole according to Method GH5 and chiral separation of the resulting racemate. Yield of final step: 12 mg, 22% (including the chiral separation), obtained as white solid. SFC conditions: Column: Phenomenex Lux Amylose-1, 50×4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 35% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar. Analytical SFC R_(T)(Amylose-1 column, 35% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.63 min, 100% ee (First eluting enantiomer). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.53 (d, J=7.8 Hz, 1H), 7.70 (t, J=1.1 Hz, 1H), 7.42-7.26 (m, 5H), 7.19 (t, J=1.2 Hz, 1H), 6.89 (t, J=1.1 Hz, 1H), 6.29 (s, 1H), 5.48 (s, 2H), 5.20-5.07 (m, 2H), 4.37-4.25 (m, 2H), 4.17 (ddd, J=14.6, 12.7, 6.7 Hz, 1H), 3.22-3.19 (m, 3H), 2.65-2.54 (m, 1H), 2.42-2.31 (m, 1H). LCMS RT=2.58 min [10 min method], m/z=446.1 [M+H]⁺.

Example 708

4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[1,5-a]pyridine-2-carboxamide

The title compound was prepared from 2-fluorophenylboronic acid according to METHOD GH6. Yield of final step: 95 mg, 69%. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (dt, J=7.0, 1.0 Hz, 1H), 8.52 (d, J=8.1 Hz, 1H), 7.64 (td, J=7.6, 1.8 Hz, 1H), 7.56 (dddd, J=8.4, 7.2, 5.3, 1.8 Hz, 1H), 7.53-7.48 (m, 1H), 7.46-7.36 (m, 3H), 7.36-7.26 (m, 2H), 7.26-7.23 (m, 1H), 7.19 (t, J=7.0 Hz, 1H), 6.80 (dd, J=2.0, 1.0 Hz, 1H), 4.91 (dt, J=11.6, 7.9 Hz, 1H), 4.59 (dd, J=11.6, 9.9 Hz, 1H), 4.44 (dd, J=9.9, 7.7 Hz, 1H), 3.33 (s, 3H). LCMS RT=5.64 min [10 min method], m/z=431.1 [M+H]⁺.

Examples 709 and 710 Method GH8

(4R)-4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5, 6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide and (4S)-4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5, 6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

To a solution of 4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[1,5-a]pyridine-2-carboxamide (88 mg, 0.20 mmol, 1.0 equiv) in acetic acid (2 mL) was added platinum(IV) oxide (5 mg, 0.020 mmol, 0.10 equiv). The reaction mixture was stirred under a balloon of hydrogen for 48 h. After this time, the mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by chiral SFC (SFC conditions: Column: CHIRALPAK IC 50×4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:Methanol (0.1% NH4OH) Isocratic: 45% B in 2.5 min Flow rate: 4 mL/min Column temperature: 40° C., BPR: 120 bar) affording arbitrarily assigned diastereomers (4R)-4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (23 mg, 26%) and (4S)-4-(2-fluorophenyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-4, 5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (17 mg, 19%).

Analytical data for the first eluting diastereomer (arbitrarily assigned S,R configuration): SFC R_(T) (CHIRALPAK IC column, 45% methanol+0.1% ammonium hydroxide isocratic elution, 2.5 min method): 0.96 min, 100% ee: 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J=8.1 Hz, 1H), 7.51-7.46 (m, 1H), 7.37-7.24 (m, 3H), 7.24-7.11 (m, 4H), 6.03 (d, J=1.0 Hz, 1H), 4.81 (dt, J=11.5, 7.9 Hz, 1H), 4.53 (dd, J=11.6, 9.9 Hz, 1H), 4.42 (dd, J=9.5, 4.7 Hz, 1H), 4.36 (dd, J=9.9, 7.7 Hz, 1H), 4.32-4.14 (m, 2H), 3.30 (s, 3H), 2.20-1.99 (m, 3H), 1.99-1.84 (m, 1H). LCMS R_(T)=5.70 min [10 min method], m/z=435.1 [M+H]⁺.

Analytical data for the second eluting diastereomer (arbitrarily assigned S,S configuration): SFC R_(T) 1.18 min, 99% ee. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J=8.1 Hz, 1H), 7.53-7.45 (m, 1H), 7.38-7.24 (m, 3H), 7.24-7.12 (m, 4H), 6.04 (d, J=0.9 Hz, 1H), 4.81 (dt, J=11.5, 7.9 Hz, 1H), 4.51 (dd, J=11.5, 9.9 Hz, 1H), 4.42 (dd, J=9.6, 4.8 Hz, 1H), 4.36 (dd, J=9.9, 7.7 Hz, 1H), 4.33-4.14 (m, 2H), 3.30 (s, 3H), 2.19-2.00 (m, 3H), 1.90 (q, J=10.1 Hz, 1H). LCMS R_(T)=5.70 min [10 min method], m/z=435.1 [M+H]⁺.

Example 711

1-(3,3-difluoropropyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[4,3-c]pyridine-6-carboxamide

The title compound was prepared according to Method GH7 carrying on the isomer isopropyl 1-(3,3-difluoroallyl)pyrazolo[4,3-c]pyridine-6-carboxylate obtained in Step 2. Yield of final step: 59 mg, 70%. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=1.1 Hz, 1H), 9.03 (d, J=7.8 Hz, 1H), 8.48 (d, J=1.0 Hz, 1H), 8.34 (t, J=1.1 Hz, 1H), 7.55-7.50 (m, 1H), 7.40-7.24 (m, 3H), 6.15 (tt, J=56.2, 4.4 Hz, 1H), 4.93 (dt, J=10.5, 8.2 Hz, 1H), 4.70 (t, J=6.8 Hz, 2H), 4.60-4.49 (m, 2H), 3.35 (s, 3H), 2.47-2.36 (m, 2H). LCMS RT=5.00 min [10 min method], m/z=416.1 [M+H]⁺.

Example 712

1-(1,1-difluoropropyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[4,3-c]pyridine-6-carboxamide

Step 1: isopropyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate

To a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (3000 mg, 15.150 mmol, 1.0 equiv) in 2-propanol (20 mL) was added triethylamine (6.33 mL, 45 mmol, 3.0 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1131 mg, 1.51 mmol, 0.10 equiv). The reaction vessel was pressurized with carbon monoxide to 120 psi. The reaction mixture was then heated to 80° C. for 16 h with stirring. After this time, the mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% isopropyl alcohol in dichloromethane) affording isopropyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate (1250 mg, 40% yield) as a red solid. LCMS RT=0.79 min [2 min method], m/z=206 [M+H]⁺.

Step 2: isopropyl 1-(1,1-difluoroallyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate and isopropyl 1-(3,3-difluoroallyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

To a solution of isopropyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate (1250 mg, 6.09 mmol, 1.0 equiv) in acetonitrile (20 mL) was added cesium carbonate (3970 mg, 12.2 mmol, 2.0 equiv) and 3-bromo-3,3-difluoropropene (0.6481 mL, 1000 mg, 6.37117 mmol, 1.05 equiv). The reaction vessel was sealed and stirred at RT for 72 hr. The mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 100% isopropyl acetate in heptane) affording isopropyl 1-(1,1-difluoroallyl)pyrazolo[4,3-c]pyridine-6-carboxylate (first to elute, 170 mg, 10% yield) (LCMS RT=1.37 min [2 min method], m/z=282 [M+H]+) and isopropyl 1-(3,3-difluoroallyl)pyrazolo[4,3-c]pyridine-6-carboxylate (second to elute, 300 mg, 18% yield) (LCMS RT=1.19 min [2 min method], m/z=282 [M+H]+) as white solids.

Step 3: isopropyl 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

To a solution of isopropyl 1-(1,1-difluoroallyl)pyrazolo[4,3-c]pyridine-6-carboxylate (170 mg, 0.6043 mmol, 1.0 equiv) in ethanol (3 mL) was added 10% palladium on carbon (64 mg, 0.06043 mmol, 0.10 equiv). The reaction vessel was placed under a balloon of hydrogen for 16 h with stirring. The reaction mixture was filtered through Celite and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 60% isopropyl acetate in heptane) affording isopropyl 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (109 mg, 64% yield) as a colorless oil. LCMS RT=1.44 min [2 min method], m/z=284 [M+H]⁺.

Step 4: sodium 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

To a solution of isopropyl 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (109 mg, 0.385 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) was added 1M sodium hydroxide (0.42 mL, 0.42 mmol, 1.1 equiv). The reaction mixture was stirred for 2 h at 50° C. After this time, the mixture was concentrated to dryness in vacuo affording sodium 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate as a brown residue which was used directly in the next reaction. LCMS RT=0.94 min [2 min method], m/z=242 [M+H]⁺.

Step 5: 1-(1,1-difluoropropyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[4,3-c]pyridine-6-carboxamide

To a solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (88 mg, 0.385 mmol, 1.0 equiv) in N,N-dimethylformamide (2 mL) was added sodium 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (101 mg, 0.385 mmol, 1.0 equiv), N,N-diisopropylethylamine (0.201 mL, 1.15 mmol, 3.0 equiv), and (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (251 mg, 0.46 mmol, 1.2 equiv). The reaction mixture was stirred for 16 h at RT. After this time, the crude mixture was loaded directly on a silica column and purified by chromatography (silica gel, 100-200 mesh, 0 to 80% isopropyl acetate in heptane) affording 1-(1,1-difluoropropyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[4,3-c]pyridine-6-carboxamide (101 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J=1.1 Hz, 1H), 9.08 (d, J=7.8 Hz, 1H), 8.74 (d, J=0.9 Hz, 1H), 8.25 (p, J=1.3 Hz, 1H), 7.58-7.48 (m, 1H), 7.38-7.25 (m, 3H), 4.92 (dt, J=11.2, 7.8 Hz, 1H), 4.65-4.46 (m, 2H), 3.35 (s, 3H), 2.86-2.70 (m, 2H), 1.10 (t, J=7.4 Hz, 3H). LCMS RT=5.75 min [10 min method], m/z=416.1 [M+H]⁺.

Example 713 Method GH6

4-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[1,5-a]pyri dine-2-carboxamide

Step 1: ethyl 4-phenylpyrazolo[1,5-a]pyridine-2-carboxylate

To a solution of ethyl 4-bromopyrazolo[1,5-a]pyridine-2-carboxylate (200 mg, 0.74 mmol, 1.0 equiv) in toluene (8 ml) was added phenylboronic acid (136 mg, 1.11 mmol, 1.5 equiv), potassium phosphate tribasic (483 mg, 2.23 mmol, 3.0 equiv), and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (22 mg, 0.045 mmol, 0.06 equiv). The mixture was degassed for 15 mins with a nitrogen stream, then to it was added chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (18 mg, 0.022 mmol, 0.03 equiv). The reaction vessel was sealed and heated to 80° C. with vigorous stirring for 1 h. The mixture was cooled to RT, filtered through Celite, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 70% isopropyl acetate in heptane) affording ethyl 4-phenylpyrazolo[1,5-a]pyridine-2-carboxylate (187 mg, 95% yield) as an off white solid.

LCMS R_(T)=1.53 min [2 min method], m/z=267 [M+H]⁺.

Step 2: sodium 4-phenylpyrazolo[1,5-a]pyridine-2-carboxylate

To a solution of ethyl 4-phenylpyrazolo[1,5-a]pyridine-2-carboxylate (187 mg, 0.70 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) was added 1M sodium hydroxide (0.8427 mL, 0.8427 mmol, 1.2 equiv). The reaction mixture was stirred overnight at RT, then was concentrated to dryness in vacuo affording sodium 4-phenylpyrazolo[1,5-a]pyridine-2-carboxylate as a white solid which was used directly in the next step. LCMS R_(T)=1.22 min [2 min method], m/z=239 [M+H]⁺.

Step 3: 4-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[1,5-a]pyri dine-2-carboxamide

To a solution of [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]ammonium chloride (80 mg, 0.35 mmol, 1.0 equiv) in DMF (2 mL) was added sodium 4-phenylpyrazolo[1,5-a]pyridine-2-carboxylate (91 mg, 0.35 mmol, 1.0 equiv), N,N-diisopropylethylamine (0.18 mL, 1.1 mmol, 3.0 equiv), and (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (230 mg, 0.42 mmol, 1.2 equiv). The reaction mixture was stirred for 16 h at RT. After this time, the crude mixture was loaded directly on a silica column and purified by chromatography (silica gel, 100-200 mesh, 0 to 80% isopropyl acetate in heptane) affording 4-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[1,5-a]pyridine-2-carboxamide (76 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (dt, J=7.0, 1.0 Hz, 1H), 8.53 (d, J=8.1 Hz, 1H), 7.76-7.67 (m, 2H), 7.61-7.45 (m, 4H), 7.41 (dd, J=7.1, 0.9 Hz, 1H), 7.38-7.22 (m, 3H), 7.22-7.13 (m, 1H), 7.07 (d, J=1.0 Hz, 1H), 4.92 (dt, J=11.4, 7.9 Hz, 1H), 4.59 (dd, J=11.6, 9.9 Hz, 1H), 4.45 (dd, J=9.9, 7.7 Hz, 1H), 3.33 (s, 3H).

LCMS RT=5.70 min [10 min method], m/z=413.1 [M+H]⁺.

Example 714

(S)—N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4-phenylpyrazolo[1,5-a]pyridine-2-carboxamide

The title compound was prepared from (S)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one according to Method GH6. Yield of final step: 94%. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (dt, J=7.0, 1.0 Hz, 1H), 8.58 (d, J=7.9 Hz, 1H), 7.77-7.69 (m, 2H), 7.62-7.53 (m, 2H), 7.53-7.45 (m, 1H), 7.40 (dd, J=7.1, 1.0 Hz, 1H), 7.17 (t, J=7.0 Hz, 1H), 7.08 (d, J=1.0 Hz, 1H), 6.14 (s, 1H), 4.41 (dt, J=11.6, 7.9 Hz, 1H), 4.29 (dd, J=14.5, 7.9 Hz, 1H), 4.20-4.05 (m, 1H), 3.23 (s, 3H), 2.68-2.56 (m, 1H), 2.41-2.30 (m, 1H), 2.18 (s, 3H). LCMS RT=4.86 min [10 min method], m/z=415.1 [M+H]⁺.

Examples 715-718 Prepared According to Method GH_Chiral_1 (See, e.g. Examples 352 and 354) Examples 719-722 Prepared According to Method GZ9 (See, e.g. Example 391) Example 723

N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

Method GZ6. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (dd, J=8.1, 1.9 Hz, 1H), 7.49 (dt, J=7.5, 1.5 Hz, 1H), 7.44-7.11 (m, 9H), 5.20 (t, J=5.0 Hz, 1H), 4.91-4.75 (m, 1H), 4.56 (ddd, J=11.5, 9.9, 4.1 Hz, 1H), 4.37 (ddd, J=9.9, 7.6, 6.0 Hz, 1H), 4.32-4.15 (m, 2H), 3.37 (q, J=5.3 Hz, 1H), 3.32-3.11 (m, 4H). LCMS RT=3.26 min [10 min method], m/z=419.1 [M+H]⁺.

Example 724

1-benzyl-N-[2-[(2-methoxyethylamino)methyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Method GZ9. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.43-7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.31 (m, 2H), 4.21-4.07 (m, 1H), 3.66 (d, J=2.1 Hz, 2H), 3.46-3.31 (m, 2H), 3.23 (s, 6H), 2.72 (t, J=5.7 Hz, 2H), 2.58 (m, 1H), 2.41-2.28 (m, 1H). LCMS: m/z=419.1 [M+H]⁺.

Example 725

(S)-1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Method GZ9. ¹H 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.51 (d, J=7.7 Hz, 1H), 7.42-7.26 (m, 5H), 6.21 (s, 1H), 5.48 (s, 2H), 4.35-4.23 (m, 2H), 4.13 (m, 1H), 3.94 (p, J=5.8 Hz, 1H), 3.57-3.32 (m, 4H), 3.18 (ds, 6H), 2.86 (m, 2H), 2.58 (m, 1H), 2.41-2.28 (m, 1H).

LCMS: m/z=465.2.

Example 726

(S)-1-benzyl-N-(2-((3-fluoroazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Method GZ9. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 5H), 6.23 (s, 1H), 5.48 (s, 2H), 5.26-5.01 (m, 1H), 4.35-4.23 (m, 2H), 4.14 (m, 1H), 3.63-3.50 (m, 4H), 3.27-3.06 (m, 5H), 2.58 (m, 1H), 2.41-2.28 (m, 1H). LCMS: m/z=453.2.

Example 727

(S)-1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was further purified by chiral SFC (Cellulose-1; 150×21.2 mm, 5 um; 35% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned (S)-1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (25.2 mg, 34.7%) as a white solid:

Analytical data for (S)-1-benzyl-N-(2-((3,3-difluoropyrrolidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide: SFC R_(T) (Cellulose-1, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.876 min, 100% purity, 100% ee. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 5H), 6.28 (s, 1H), 5.48 (s, 2H), 4.31 (qd, J=7.9, 2.4 Hz, 2H), 4.15 (ddd, J=14.5, 12.6, 6.6 H, 1H), 3.57 (q, J=13.4 Hz, 2H), 3.23 (s, 3H), 2.91 (t, J=13.4 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H), 2.67-2.54 (m, 1H), 2.43-2.10 (m, 3H). LC-MS R_(T)=2.86 min, m/z=485.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.86 min, ESI+ found [M+H]=485.2.

Example 728

(S)-1-benzyl-N-(2-(((2-methoxyethyl)amino)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-(((2-methoxyethyl)amino)methyl)-4-methyl-5-oxo-5, 6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was further purified by chiral SFC (Cellulose-1; 150×21.2 mm, 5 um; 30% methanol isocratic elution with Carbon Dioxide) affording

(S)-1-benzyl-N-(2-(((2-methoxyethyl)amino)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (7.4 mg, 18.5%) as a white solid:

Analytical data for (S)-1-benzyl-N-(2-(((2-methoxyethyl)amino)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide: SFC R_(T) (Cellulose-1, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.805 min, 99.7% purity, 99.4% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.43-7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.31 (m, 2H), 4.21-4.07 (m, 1H), 3.66 (d, J=2.1 Hz, 2H), 3.46-3.31 (m, 2H), 3.23 (s, 6H), 2.72 (t, J=5.7 Hz, 2H), 2.58 (m, 1H), 2.41-2.28 (m, 1H). LC-MS R_(T)=2.65 min, m/z=453.2 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.65 min, ESI+ found [M+H]=453.2.

Example 729

(8R)—N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-8-phenyl-5,6,7,8-tetrahydr o-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

Further purification of Example 723. ¹H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.6, 1.9 Hz, 1H), 7.42-7.18 (m, 9H), 5.20 (d, J=5.3 Hz, 1H), 4.81 (dt, J=11.4, 7.8 Hz, 1H), 4.56 (dd, J=11.6, 9.8 Hz, 1H), 4.36 (dd, J=9.9, 7.7 Hz, 1H), 4.32-4.15 (m, 2H), 3.37 (q, J=5.1 Hz, 1H), 3.32-3.11 (m, 4H). LCMS: m/z=419.1 (3.26 min).

Example 730 Method GZ17

7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

Step 1: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazol o[1,5-a]pyrazine-2-carboxamide was prepared from (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one and 3-phenylpyrazin-2-amine according to Method GZ5. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid). Yield of final step: 35.5 mg, 22.9%. ¹H NMR (400 MHz, DMSO-d6) δ 9.15-9.03 (m, 2H), 8.84-8.75 (m, 2H), 8.47 (d, J=4.5 Hz, 1H), 7.70-7.58 (m, 3H), 7.55 (dd, J=7.6, 1.9 Hz, 1H), 7.40-7.23 (m, 3H), 4.98 (dt, J=11.5, 7.8 Hz, 1H), 4.73 (dd, J=11.6, 9.8 Hz, 1H), 4.51 (dd, J=9.8, 7.7 Hz, 1H), 3.35 (s, 3H).

LC-MS R_(T)=5.04 min, m/z=415.1 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 5.04 min, ESI+ found [M+H]=415.1

Step 2: N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

To a solution of (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-[1,2,4]triazol o[1,5-a]pyrazine-2-carboxamide (368 mg, 0.88 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added platinum(iv) oxide (20.2 mg, 0.088 mmol). The reaction mixture stirred under a balloon of hydrogen gas for 16 h at RT, then was filtered through Celite and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% methanol in dichloromethane) to afford N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetra hydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide (216 mg, 52% Yield) as a tan solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (dd, J=8.1, 1.9 Hz, 1H), 7.49 (dt, J=7.5, 1.5 Hz, 1H), 7.44-7.11 (m, 9H), 5.20 (t, J=5.0 Hz, 1H), 4.91-4.75 (m, 1H), 4.56 (ddd, J=11.5, 9.9, 4.1 Hz, 1H), 4.37 (ddd, J=9.9, 7.6, 6.0 Hz, 1H), 4.32-4.15 (m, 2H), 3.37 (q, J=5.3 Hz, 1H), 3.32-3.11 (m, 4H). LC-MS R_(T)=3.26 min, m/z=419.1 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.26 min, ESI+ found [M+H]=419.1

Step 3: 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

To a solution of N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetra hydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide (83 mg, 0.198 mmol) in dichloroethane (1.5 mL) was added formaldehyde (13.31 mol/L) in water (0.05 mL, 0.595 mmol), then added acetic acid (0.04 mL, 0.595 mmol), then added sodium triacetoxyborohydride (168 mg, 0.793 mmol) and allowed to stir for overnight. The reaction mixture was made basic with the addition of saturated aq. NaHCO₃ solution (10 mL) and stirring for 20 min. Extracted with DCM (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo, The crude residue was further purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid, column: Gemini-NX C18 10 um, 50×30 mm) to afford 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide (14.7 mg, 17%) as a tan solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J=8.0, 5.5 Hz, 1H), 7.48 (dt, J=7.6, 2.0 Hz, 1H), 7.42-7.17 (m, 9H), 4.85-4.72 (m, 1H), 4.61-4.49 (m, 2H), 4.45-4.27 (m, 3H), 3.28 (d, J=1.9 Hz, 4H), 3.00-2.87 (m, 1H), 2.21 (s, 3H). LC-MS R_(T)=4.29 min, m/z=433.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.29 min, ESI+ found [M+H]=433.2.

Example 731

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-(trifluoromethyl)-5, 6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-carboxamide was prepared from 3-(trifluoromethyl)pyrazin-2-amine according to Method GZ6. Yield of final step: 6 mg, 86%, isolated as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (dd, J=7.9, 2.3 Hz, 1H), 7.57-7.45 (m, 1H), 7.39-7.16 (m, 4H), 5.16-4.99 (m, 1H), 4.85 (dtd, J=11.5, 7.8, 3.8 Hz, 1H), 4.60 (dt, J=11.5, 9.7 Hz, 1H), 4.43 (ddd, J=9.9, 7.6, 6.8 Hz, 1H), 4.25 (m, 1H), 4.21-4.04 (m, 1H), 3.68 (m, 1H), 3.31 (s, 3H), 3.27-3.19 (m, 1H). LC-MS R_(T)=3.87 min, m/z=411.1 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.87 min, ESI+ found [M+H]=411.1

Example 732

(S)-1-benzyl-N-(2-(hydroxymethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-(hydroxymethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was further purified by chiral SFC (Chiralpak AD, 150×21.2 mm, 30% methanol isocratic elution with Carbon Dioxide) affording (S)-1-benzyl-N-(2-(hydroxymethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (11.6 mg, 46%) as a white solid.

Analytical data (S)-1-benzyl-N-(2-(hydroxymethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide: SFC R_(T) (Chiralpak AD, 30% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.824 min, 99.8% purity, 99.6% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 5H), 6.28 (s, 1H), 5.48 (s, 2H), 5.10 (t, J=5.8 Hz, 1H), 4.45-4.24 (m, 4H), 4.15 (m, 1H), 3.24 (s, 3H), 2.58 (m, 1H), 2.41-2.28 (m, 1H). LC-MS R_(T)=3.14 min, m/z=396.1 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.14 min, ESI+ found [M+H]=396.1.

Example 733

(S)-1-benzyl-N-(4-methyl-5-oxo-2-(((2,2,2-trifluoroethyl)amino)methyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(4-methyl-5-oxo-2-(((2,2,2-trifluoroethyl)amino)methyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was prepared from 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide and 2,2,2-trifluoroethanamine; hydrochloride according to Method GZ8. The crude residue was further purified by chiral SFC (Chiralpak OX; 150×21.2 mm, 5 um; 40% methanol isocratic elution with Carbon Dioxide) affording (S)-1-benzyl-N-(4-methyl-5-oxo-2-(((2,2,2-trifluoroethyl)amino)methyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (5 mg, 8.3%) as a white solid:

Analytical data for (S)-1-benzyl-N-(4-methyl-5-oxo-2-(((2,2,2-trifluoroethyl)amino)methyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide: SFC R_(T) (Chiralpak OX, 35% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 1.177 min, 100% purity, 100% ee. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 5H), 6.28 (s, 1H), 5.48 (s, 2H), 4.31 (m, 2H), 4.15 (m, 1H), 3.79-3.64 (m, 2H), 3.33-3.15 (m, 4H), 2.77 (p, J=6.9 Hz, 1H), 2.59 (m, 1H), 2.50-2.29 (m, 1H). LCMS R_(T)=3.18 min, m/z=477.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.18 min, ESI+ found [M+H]=477.2.

Examples 734 and 735

(R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide and (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (1:1)

N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7,8-tetra hydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide was further purified by chiral SFC (Cellulose-3; 151×21.2 mm, 5 um; 15% methanol isocratic elution with Carbon Dioxide) affording arbitrarily assigned diastereomers (R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (14.7 mg, 9.4%) and (S)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (10 mg, 6.4%) as white solids:

Analytical data for the first eluting diastereomer (arbitrarily assigned R, S configuration): SFC R_(T) (Cellulose-3, 15% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.603 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=7.9 Hz, 1H), 7.49 (dd, J=7.6, 2.0 Hz, 1H), 7.40-7.18 (m, 6H), 7.09-7.01 (m, 2H), 5.57 (t, J=5.9 Hz, 1H), 4.80 (dt, J=11.5, 7.8 Hz, 1H), 4.57 (dd, J=11.6, 9.9 Hz, 1H), 4.38 (dd, J=9.9, 7.6 Hz, 1H), 3.30 (s, 3H), 3.11-2.89 (m, 2H), 2.49-2.32 (m, 1H), 2.11-1.98 (m, 1H), 1.87 (h, J=5.9, 5.4 Hz, 2H). LCMS R_(T)=11.60 min, m/z=418.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 30 mins) retention time 11.60 min, ESI+ found [M+H]=418.2

Analytical data for the second eluting diastereomer (arbitrarily assigned S, S configuration): SFC R_(T) (Cellulose-3, 15% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.746 min, 99.4% purity, 98.8% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.5, 2.0 Hz, 1H), 7.40-7.19 (m, 6H), 7.09-7.01 (m, 2H), 5.57 (t, J=5.9 Hz, 1H), 4.80 (dt, J=11.5, 7.8 Hz, 1H), 4.56 (dd, J=11.5, 9.9 Hz, 1H), 4.38 (dd, J=9.9, 7.7 Hz, 1H), 3.44-3.20 (s, 3H), 3.10-2.90 (m, 2H), 2.38 (dt, J=11.5, 6.4 Hz, 1H), 2.10-1.98 (m, 1H), 1.86 (p, J=6.3 Hz, 2H). LCMS R_(T)=11.72 min, m/z=418.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 30 mins) retention time 11.72 min, ESI+ found [M+H]=418.1.

Example 736 Method GZ20

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl) imidazo[1,2-a]pyridine-2-carboxamide

To a solution of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (100 mg, 0.520 mmol) and 5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (126 mg, 0.546 mmol) in N,N-dimethylformamide (2 mL) was added HATU (224 mg, 0.752 mmol), and N,N-diisopropylethylamine (0.28 mL, 1.56 mmol. The reaction mixture was stirred overnight at RT, then was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid) to afford (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide (169 mg, 80%) as tan solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=8.0 Hz, 1H), 8.30 (q, J=1.8 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.60-7.48 (m, 2H), 7.30 (m, 3H), 4.91 (dt, J=11.4, 7.9 Hz, 1H), 4.60 (dd, J=11.5, 9.9 Hz, 1H), 4.47 (dd, J=9.9, 7.7 Hz, 1H), 3.34 (s, 3H). LCMS R_(T)=6.00 min, m/z=405.0 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 6.00 min, ESI+ found [M+H]=405.0.

Example 737

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-(trifluoromethyl) imidazo[1,2-a]pyridine-2-carboxamide

(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide was prepared corresponding from (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride, and 8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid according to Method GZ20. The residue was purified by preparative RP-HPLC (20-60% acetonitrile in water+0.1% formic acid). Yield of final step: 175 mg, 83%. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=6.8 Hz, 1H), 8.57 (s, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.86 (dt, J=7.3, 1.2 Hz, 1H), 7.55-7.46 (m, 1H), 7.39-7.23 (m, 3H), 7.14 (t, J=7.0 Hz, 1H), 4.91 (dt, J=11.3, 7.7 Hz, 1H), 4.64-4.45 (m, 2H), 3.35 (s, 3H). LC-MS R_(T)=4.81 min, m/z=405.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 4.81 min, ESI+ found [M+H]=405.1.

Example 738

1-benzyl-N-[(6R)-4-methyl-2-(3-morpholinopropyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Further purification of Example 662. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.38-7.32 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.54-4.49 (m, 1H), 4.33-4.30 (m, 1H), 4.27-4.21 (m, 1H), 3.69 (t, J=4.8 Hz, 4H), 3.33 (s, 3H), 2.83-2.80 (m, 1H), 2.66-2.62 (m, 2H), 2.48-2.40 (m, 6H), 2.26-2.24 (m, 1H), 1.89-1.86 (m, 2H).

Example 739 WX Method 211

1-benzyl-N-[(6S)-2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: 1-benzyl-N-[2-[(E)-3-(3,3-difluoropyrrolidin-1-yl)prop-1-enyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

To a solution of [(E)-3-[6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]allyl]methanesulfonate (20 mg, 0.04 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (28 mg, 0.20 mmol) and 3,3-difluoropyrrolidine hydrochloride (17 mg, 0.12 mmol). The reaction mixture was stirred at 35° C. for 12 h and then poured into water (15 mL). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 1-benzyl-N-[2-[(E)-3-(3,3-difluoropyrrolidin-1-yl)prop-1-enyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (18 mg, 88%) as a yellow oil. LC-MS R_(T)=0.579 min, m/z=511.1 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.579 min, ESI+ found [M+H]=511.1.

Step 2: 1-benzyl-N-[(6S)-2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-N-[2-[(E)-3-(3,3-difluoropyrrolidin-1-yl)prop-1-enyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (18 mg, 0.04 mmol) and Pallidium on carbon (10%, 19 mg) in ethyl acetate (10 mL) was hydrogenated (15 psi) for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% NH₃.H₂O in water) to give 1-benzyl-N-[2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (13 mg, 72%) as a white solid. The racemic material (50 mg, from 2 batches) was further separated by chiral SFC to give: 1-benzyl-N-[(6 S)-2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, Retention time 4.500 min) (8.1 mg, 16%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.39-7.33 (m, 5H), 6.17 (s, 1H), 5.48 (s, 2H), 4.54-4.49 (m, 1H), 4.32-4.30 (m, 1H), 4.26-4.21 (m, 1H), 3.33 (s, 3H), 3.07-3.03 (m, 2H), 2.91-2.83 (m, 3H), 2.68-2.65 (m, 4H), 2.36-2.27 (m, 3H), 1.91-1.87 (m, 2H). LC-MS R_(T)=1.639 min, m/z=513.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.639 min, ESI+ found [M+H]=513.2.

1-benzyl-N-[(6R)-2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, Retention time=5.268 min) (7.7 mg, 15%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (br. s, 1H), 7.39-7.33 (m, 5H), 6.17 (s, 1H), 5.48 (s, 2H), 4.54-4.49 (m, 1H), 4.32-4.30 (m, 1H), 4.25-4.22 (m, 1H), 3.33 (s, 3H), 3.23-3.20 (m, 2H), 3.07 (br. s, 2H), 2.83-2.80 (m, 3H), 2.68 (t, J=7.2 Hz, 2H), 2.40-2.37 (m, 2H), 2.35-2.25 (m, 1H), 1.95-1.91 (m, 2H). LC-MS R_(T)=1.647 min, m/z=513.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.647 min, ESI+ found [M+H]=513.2.

SFC condition: column: chiralcel OD-3 (100×4.6 mm), 3 um mobile phase: A:CO2; B: ethanol (0.05% DEA) gradient: from 5 to 40 of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example 740 WX Method 182

1-benzyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazole-3-carboxamide

Step 1: methyl 1-benzylpyrazole-3-carboxylate

To a solution of methyl 1H-pyrazole-3-carboxylate (200 mg, 1.59 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (658 mg, 4.76 mmol) and benzyl bromide (326 mg, 1.9 mmol). The mixture was stirred at 25° C. for 12 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give methyl 1-benzylpyrazole-3-carboxylate (240 mg, 70%) as a white solid, used as is in the next step.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.495 min, ESI+ found [M+H]=217.1.

Step 2: 1-benzylpyrazole-3-carboxylic acid

A mixture of methyl 1-benzylpyrazole-3-carboxylate (240 mg, 1.11 mmol) and lithium hydroxide hydrate (133 mg, 5.55 mmol) in ethanol/water (13 mL, 8:1) was stirred at 25° C. for 12 h. The solution was diluted with water (10 mL) and adjusted to pH=4-5 by addition of 2M HCl. The resulting solid was collected by filtration and dried under reduced pressure to give crude 1-benzylpyrazole-3-carboxylic acid (170 mg, 76%) as a white solid, used in the next step without further purification.

Step 3: 1-benzyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazole-3-carboxamide

A mixture of 1-benzylpyrazole-3-carboxylic acid (60 mg, 0.28 mmol), (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 0.28 mmol), 1-hydroxybenzotriazole (56 mg, 0.42 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (80 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 27-57%/0.05% ammonium hydroxide in water) to afford 1-benzyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazole-3-carboxamide (66.9 mg, 66%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.71 (d, J=2.4 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.35-7.26 (m, 5H), 6.74 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 5.40 (s, 2H), 4.57-4.52 (m, 1H), 4.46-4.44 (m, 1H), 4.34-4.31 (m, 1H), 3.36 (s, 3H), 2.89-2.82 (m, 1H), 2.34-2.28 (m, 1H). LC-MS R_(T)=0.755 min, m/z=365.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.755 min, ESI+ found [M+H]=365.0.

Example 741

1-benzyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 182. The crude was purified by RP-HPLC (acetonitrile 27-57%/0.05% ammonium hydroxide in water) to give 1-benzyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]pyrazole-3-carboxamide (66.6 mg, 68%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.71 (s, 1H), 7.36-7.25 (m, 5H), 6.75 (s, 1H), 6.39-6.34 (m, 1H), 5.40 (s, 2H), 4.66-4.65 (m, 1H), 4.44-4.34 (m, 2H), 3.36 (s, 3H), 2.92-2.81 (m, 1H), 2.39-2.37 (m, 4H). LC-MS R_(T)=0.764 min, m/z=379.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.764 min, ESI+ found [M+H]=379.0.

Examples 742 and 744 WX Method 186

(1S)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide and (1R)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide

Step 1: 6-chloro-1-methyl-1-(trifluoromethyl)furo[3,4-c]pyridin-3(1H)-one

To a solution of 2,2,6,6-tetramethylpiperidine (13.5 g, 95.2 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (2.5 M in hexanes, 38.0 mL, 95.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 6-chloronicotinic acid (5.0 g, 31.7 mmol) was added. The reaction mixture was stirred at −78° C. for another 2 h and 1,1,1-trifluoroacetone (10.7 g, 95 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 24 h and quenched by addition of saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 6-chloro-1-methyl-1-(trifluoromethyl)furo[3,4-c]pyridin-3(1H)-one (6.0 g, 75%) as yellow oil, used as is in the next step.

Step 2: 2-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)-1,1,1-trifluoropropan-2-ol

To a solution of 6-chloro-1-methyl-1-(trifluoromethyl)furo[3,4-c]pyridin-3(1H)-one (3.0 g, 11.9 mmol) in tetrahydrofuran (60 mL) was added lithium aluminium hydride (881 mg, 24 mmol) in portions at −78° C. After addition, the mixture was slowly warmed to 0° C. and stirred at 0° C. for 30 min. The mixture was quenched with addition of water (0.05 mL), 10% NaOH (0.05 mL) and followed by water (0.15 mL). The resulting mixture was added anhydrous sodium sulphate (20 g) and stirred for 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 2-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)-1,1,1-trifluoropropan-2-ol (400 mg, 13%) as white solid, used as is in the next step.

Step 3: 6-chloro-1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine

To a solution of N1,N1,N2,N2-tetramethyldiazene-1,2-dicarboxamide (808 mg, 4.7 mmol) in toluene (40 mL) was added tri-n-butylphosphine (950 mg, 4.7 mmol) and 2-[2-chloro-5-(hydroxymethyl)-4-pyridyl]-1,1,1-trifluoro-propan-2-ol (400 mg, 1.6 mmol) under nitrogen atmosphere. The mixture was stirred at 25° C. for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 6-chloro-1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine (200 mg, 54%).

LC-MS R_(T)=1.5 min, m/z=238.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.98 min, ESI+ found [M+H]=238.1.

Step 4: methyl 1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate

A mixture of 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (55 mg, 0.08 mmol), 6-chloro-1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine (180 mg, 0.76 mmol) and triethylamine (230 mg, 2.27 mmol) in methanol (50 mL) was heated at 70° C. under the atmosphere of CO (35 psi) for 15 h. After cooling to room temperature, the reaction mixture was filtered and the filtrated was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (150 mg, 76%) as a light yellow oil, used as is in the next step. LC-MS R_(T)=0.78 min, m/z=261.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.78 min, ESI+ found [M+H]=261.9.

Step 5: 1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid

A mixture of methyl 1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (140 mg, 0.54 mmol) and potassium hydroxide (60 mg, 1.07 mmol) in ethanol (4 mL) and water (1 mL) was stirred at 25° C. for 12 h. The mixture was added 1N HCl (3 mL) and concentrated under reduced pressure. The crude was dissolved in methanol (20 mL) and filtered. The filtrate was concentrated under reduced pressure to afford the crude 1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (120 mg, 91%) as a yellow solid, used in the next step without further purification.

Step 6: (1S)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide and (1R)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (40 mg, 0.21 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (5.6 mg, 0.04 mmol), 1-methyl-1-(trifluoromethyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid (51 mg, 0.21 mmol) and N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine hydrochloride (40 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 48% to 78%/0.05% ammonium hydroxide in water) to afford 1-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[1,4]oxazepin-3-yl)-1-(trifluoro methyl)-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (55 mg, 63%) as a white solid. This racemic material was further separated by chiral SFC to afford:

(1S)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide (Peak 1, retention time 4.376 min) (17.9 mg, 31%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, J=8.0 Hz, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 7.27-7.26 (m, 3H), 5.31 (s, 2H), 5.14-5.05 (m, 1H), 4.79 (t, J=8.0 Hz, 1H), 4.36-4.27 (m, 1H), 3.46 (s, 3H), 1.71 (s, 3H). LC-MS R_(T)=1.084 min, m/z=422.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 2 mins) retention time 1.084 min, ESI+ found [M+H]=422.2.

(1R)-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide (Peak 2, retention time 5.736 min) (19.1 mg, 34%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, J=7.2 Hz, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 7.26 (s, 3H), 5.31 (s, 2H), 5.15-5.05 (m, 1H), 4.79 (t, J=8.0 Hz, 1H), 4.33-4.27 (m, 1H), 3.46 (s, 3H), 1.71 (s, 3H). LC-MS R_(T)=1.092 min, m/z=422.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 2 mins) retention time 1.092 min, ESI+ found [M+H]=422.2.

SFC condition: Column: Chiralpak AD (250 mm*30 mm, 10 um) Mobile phase: A: CO₂ B: methanol (0.10% NH₃H₂O), supercritical CO₂/EtOH+NH₃H₂O=45/45; 80 mL/min.

Examples 743 and 745 WX Method 188

(7S)-7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide and (7R)-7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide

Step 1: 2-chloro-7-methyl-7-(trifluoromethyl)furo[3,4-d]pyrimidin-5(7H)-one

To a solution of 2,2,6,6-tetramethylpiperidine (27.0 g, 190.4 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium (2.5 M in hexanes, 76.0 mL, 190.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h and 2-chloropyrimidine-5-carboxylic acid (10.0 g, 63.3 mmol) in THF (100 mL) was added. The reaction mixture was stirred at −78° C. for another 2.5 h and 1,1,1-trifluoroacetone (21.4 g, 190.0 mmol) was added. After addition, the reaction mixture was stirred at 25° C. for 24 h and quenched by addition of saturated ammonium chloride (100 mL). The mixture was adjusted to pH=2-3 by addition of 2 M HCl (200 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 2-chloro-7-methyl-7-(trifluoromethyl)furo[3,4-d]pyrimidin-5(7H)-one (2.5 g, 16%) as yellow oil, used as is in the next step.

Step 2: 2-chloro-7-methyl-7-(trifluoromethyl)-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol

To a solution of 2-chloro-7-methyl-7-(trifluoromethyl)furo[3,4-d]pyrimidin-5(7H)-one (2.5 g, 9.9 mmol) in toluene (60 mL) was added diisobutylaluminum hydride (1.0 M in toluene, 20.0 mL, 20.0 mmol) dropwise at −78° C. After addition, the mixture was stirred at −78° C. for 2 h and then quenched by addition of water (0.05 mL), 10% NaOH (0.05 mL) and followed by H₂O (0.15 mL). The mixture was dried with Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 2-chloro-7-methyl-7-(trifluoromethyl)-5,7-dihydrofuro[3,4-d]pyrimidin-5-ol (1.2 g, 48%) as a yellow oil. LCMS R_(T)=0.622 min, m/z=254.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.622 min, ESI+ found [M+H]=254.9.

Step 3: 2-(2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)-1,1,1-trifluoropropan-2-ol

A mixture of 2-chloro-7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidin-5-ol (600 mg, 2.36 mmol) in trifluoroacetic acid (2.69 g, 23.57 mmol) was stirred at 0° C. for 30 min and then triethylsilane (2.74 g, 23.57 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford 2-[2-chloro-5-(hydroxymethyl)pyrimidin-4-yl]-1,1,1-trifluoro-propan-2-ol (300 mg, 50%) as a yellow oil.

Step 4: 2-chloro-7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine

To a solution of 2-[2-chloro-5-(hydroxymethyl)pyrimidin-4-yl]-1,1,1-trifluoro-propan-2-ol (300 mg, 1.17 mmol) in toluene (5 mL) was added tri-n-butylphosphine (355 mg, 1.75 mmol) and N1,N1,N2,N2-tetramethyldiazene-1,2-dicarboxamide (302 mg, 1.75 mmol). The reaction mixture was stirred at 20° C. for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 2-chloro-7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine (120 mg, 43%). LCMS R_(T)=0.692 min, m/z=239.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.692 min, ESI+ found [M+H]=239.0.

Step 5: methyl 7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylate

A mixture of 2-chloro-7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine (100 mg, 0.42 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (31 mg, 0.04 mmol) and triethylamine (212 mg, 2.1 mmol) in methanol (20 mL) was heated to 80° C. for 8 h under CO (45 psi). After cooled, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was then purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 100% ethyl acetate in petroleum ether) to afford methyl 7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylate (80 mg, 73%) as a light yellow oil, used as is in the next step.

Step 6:7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylicacid

A mixture of methyl 7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylate (80 mg, 0.31 mmol) and lithium hydroxide monohydrate (128 mg, 3.05 mmol) in tetrahydrofuran (5 mL)/water (3 mL) was stirred at 20° C. for 2 h. The mixture was acidified by addition of 1N HCl (3 mL) and concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and filtered. The filtrate was concentrated under reduced pressure to afford the crude 7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylic acid (60 mg, 79%) as a yellow solid, used as is in the next step.

Step 7: (7S)-7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide and (7R)-7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide

A mixture of (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (28 mg, 0.15 mmol), 7-methyl-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxylic acid (30 mg, 0.12 mmol), 1-hydroxybenzotriazole (20 mg, 0.15 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (28 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 32% to 62%/0.05% ammonium hydroxide in water) to afford 7-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(trifluoro methyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide (30 mg, 59%) as a white solid. The racemic material was further separated by chiral SFC to give:

(7S)-7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide (Peak 1, retention time 5.298 min) (10.7 mg, 36%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 7.46-7.43 (m, 1H), 7.34-7.24 (m, 3H), 5.32 (s, 2H), 5.04-4.96 (m, 1H), 4.72-4.67 (m, 1H), 4.48-4.42 (m, 1H), 3.44 (s, 3H), 1.76 (s, 3H). LCMS R_(T)=0.817 min, m/z=423.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.817 min, ESI+ found [M+H]=423.0.

(7R)-7-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide (Peak 2, retention time 6.174 min) (11.7 mg, 39%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 7.46-7.43 (m, 1H), 7.34-7.24 (m, 3H), 5.32 (s, 2H), 5.04-4.96 (m, 1H), 4.72-4.67 (m, 1H), 4.48-4.42 (m, 1H), 3.44 (s, 3H), 1.76 (s, 3H). LCMS R_(T)=0.824 min, m/z=423.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.824 min, ESI+ found [M+H]=423.0.

SFC condition: Column: ChiralCel (OD-H 150×4.6 mm I.D., 5 um) Mobile phase: A: CO₂ B:Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, Flow rate: 2.5 mL/min Column temperature: 40° C.

Examples 746 and 748

(1S)-1-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide and (1R)-1-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide

Amide coupling prepared in a similar fashion to WX Method 184. The crude was purified by RP-HPLC (acetonitrile 48-78%/0.05% ammonia hydroxidein water) to give 1-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4, 5-tetrahydro-1-benzazepin-3-yl]-1-(trifluoromethyl)-3H-furo[3,4-c]pyridine-6-carboxamide (55 mg, 63%) as a white solid. The racemate was further separated by chiral SFC to afford:

(1S)-1-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-1-(trifluoro methyl)-3H-furo[3,4-c]pyridine-6-carboxamide (Peak 1, retention time 3.756 min) (18.7 mg, 34%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J=6.8 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.17 (s, 1H), 6.91-6.82 (m, 2H), 5.31 (s, 2H), 4.79-4.70 (m, 1H), 3.12-3.01 (m, 1H), 2.96-2.85 (m, 1H), 2.80-2.72 (m, 1H), 2.21-2.10 (m, 1H), 1.72 (s, 3H). LC-MS R_(T)=1.056 min, m/z=442.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 2 mins) retention time 1.056 min, ESI+ found [M+H]=442.2.

(1R)-1-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-1-(trifluoro methyl)-3H-furo[3,4-c]pyridine-6-carboxamide (Peak 2, retention time 5.978 min) (15.6 mg, 28%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J=7.2 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.17 (s, 1H), 6.91-6.82 (m, 2H), 5.31 (s, 2H), 4.79-4.70 (m, 1H), 3.12-3.01 (m, 1H), 2.96-2.85 (m, 1H), 2.80-2.72 (m, 1H), 2.21-2.10 (m, 1H), 1.72 (s, 3H). LC-MS R_(T)=1.068 min, m/z=442.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 2 mins) retention time 1.068 min, ESI+ found [M+H]=442.2.

SFC conditions: Column: Chiralpak AD 150×4.6 mm I.D., 3 um, Mobile phase: 25% methanol (0.05% DEA) in CO₂, Flow rate: 2.4 mL/min, Column temp.: 40° C.

Examples 747 and 749

(7S)-7-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide and (7R)-7-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-7-(trifluoromethyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide

Amide coupling prepared in a similar fashion to WX Method 188. The crude was purified by RP-HPLC (acetonitrile 32% to 62%/0.05% ammonium hydroxide in water) to give N—((S)-7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-7-methyl-7-(trifluoromethyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamide (30 mg, 56%) as a white solid. The racemate was separated by chiral SFC to afford:

(7S)-7-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-7-(trifluoro methyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide (Peak 1, retention time 3.801 min) (9.1 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H), 7.04-6.99 (m, 2H), 5.32 (s, 2H), 4.66-4.61 (m, 1H), 3.04-2.98 (m, 1H), 2.87-2.75 (m, 2H), 2.28-2.23 (m, 1H), 1.76 (s, 3H). LCMS R_(T)=0.799 min, m/z=443.0 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.799 min, ESI+ found [M+H]=443.0.

(7R)-7-methyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-7-(trifluoro methyl)-5H-furo[3,4-d]pyrimidine-2-carboxamide (Peak 2, retention time 4.334 min) (9.9 mg, 33%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H), 7.04-6.99 (m, 2H), 5.32 (s, 2H), 4.66-4.61 (m, 1H), 3.04-2.98 (m, 1H), 2.87-2.75 (m, 2H), 2.28-2.23 (m, 1H), 1.76 (s, 3H). LCMS R_(T)=0.803 min, m/z=443.0 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.803 min, ESI+ found [M+H]=443.0.

SFC condition: Column: ChiralPak (AD-3 150×4.6 mm I.D., 3 um) Mobile phase: A: CO2 B:Methanol (0.05% DEA) Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, Flow rate: 2.5 mL/min Column temperature: 40° C.

Example 750 WX Method 184

1-benzyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]imidazole-4-carboxamide

Step 1: methyl 1-benzylimidazole-4-carboxylate

To a solution of methyl 4-imidazolecarboxylate (500 mg, 3.96 mmol) in acetonitrile (10 mL) was added triethylamine (482 mg, 4.76 mmol) and benzyl bromide (678 mg, 3.96 mmol). The mixture was stirred at 25° C. for 12 h and then concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 20-50%/0.05% ammonium hydroxide in water) to give methyl 1-benzylimidazole-4-carboxylate (118 mg, 14%) as a white solid, used as is in the next step. LC-MS R_(T)=1.273 min, m/z=217.1 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.273 min, ESI+ found [M+H]=217.1.

Step 2: 1-benzylimidazole-4-carboxylic acid

A mixture of methyl 1-benzylimidazole-4-carboxylate (90 mg, 0.42 mmol) and lithium hydroxide hydrate (50 mg, 2.08 mmol) in ethanol/water (9 mL, 8:1) was stirred at 25° C. for 12 h. The solution was diluted with water (10 mL) and adjusted to pH=4-5 by addition of 2M HCl. The resulting solid was collected by filtration and dried under reduced pressure to give crude 1-benzylimidazole-4-carboxylic acid (60 mg, 71%) as a white solid, used in the next step without further purification.

Step 3: 1-benzyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]imidazole-4-carboxamide

A mixture of 1-benzylimidazole-4-carboxylic acid (34 mg, 0.17 mmol), (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (30 mg, 0.17 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (48 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 7-37%/0.05% ammonium hydroxide in water) to afford 1-benzyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]imidazole-4-carboxamide (14.5 mg, 24%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.16 (s, 1H), 8.10 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.42-7.41 (m, 5H), 6.29 (d, J=2.0 Hz, 1H), 5.44 (s, 2H), 4.44-4.37 (m, 2H), 4.25-4.22 (m, 1H), 3.25 (s, 3H), 2.70-2.65 (m, 1H), 2.27-2.22 (m, 1H). LC-MS R_(T)=0.679 min, m/z=365.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.679 min, ESI+ found [M+H]=365.1.

Example 751

1-benzyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]imidazole-4-carboxamide

Amide coupling prepared in a similar fashion to WX Method 184. The crude was purified by RP-HPLC (acetonitrile 10-40%/0.05% ammonium hydroxide in water) to give 1-benzyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]imidazole-4-carboxamide (21.5 mg, 37%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.21 (s, 1H), 8.16 (s, 1H), 7.47-7.42 (m, 5H), 6.28 (s, 1H), 5.48 (s, 2H), 4.58-4.53 (m, 1H), 4.39-4.27 (m, 2H), 3.30 (s, 3H), 2.77-2.71 (m, 1H), 2.32-2.28 (m, 4H). LC-MS R_(T)=0.709 min, m/z=379.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.709 min, ESI+ found [M+H]=379.1

Example 752 WX Method 199

1-benzyl-N-[(6S)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl (4-methyl-2-(2-morpholinoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of 2-[6-(tert-butoxycarbonylamino)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]ethyl methanesulfonate (200 mg, 0.50 mmol) and morpholine (216 mg, 2.48 mmol) in N,N-dimethylformamide (10 mL) was heated to 50° C. for 6 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford tert-butyl N-[4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (150 mg, 77%) as a colorless oil, used as is in the next step.

Step 2: 6-amino-4-methyl-2-(2-morpholinoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride

To a solution of tert-butyl N-[4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (150 mg, 0.38 mmol) in ethyl acetate (5 mL) was added hydrochloric acid (4.0 M in ethyl acetate, 4.0 mL, 16.0 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated under reduced pressure to afford crude 6-amino-4-methyl-2-(2-morpholinoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride (120 mg, 96%) as a white solid, used in the next step without further purification.

Step 3: 1-benzyl-N-[(6S)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (40 mg, 0.20 mmol), 6-amino-4-methyl-2-(2-morpholinoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride (60 mg, 0.18 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (38 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 35-65%/0.05% NH₄OH in water) to afford 1-benzyl-N-[4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (70 mg, 81%) as a white solid. The racemic material was further separated by chiral SFC to give:

1-benzyl-N-[(6S)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 5.064 min) (23 mg, 32%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.37-7.34 (m, 5H), 6.20 (s, 1H), 5.48 (s, 2H), 4.53-4.50 (m, 1H), 4.33-4.31 (m, 1H), 4.23-4.21 (m, 1H), 3.73-3.71 (m, 4H), 3.33 (s, 3H), 2.86-2.81 (m, 3H), 2.72-2.67 (m, 2H), 2.58-2.52 (m, 4H), 2.26-2.24 (m, 1H).

LCMS R_(T)=0.653 min, m/z=479.2 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.653 min, ESI+ found [M+H]=479.2.

1-benzyl-N-[(6R)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 6.035 min) (22.7 mg, 32%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.37-7.34 (m, 5H), 6.20 (s, 1H), 5.48 (s, 2H), 4.53-4.50 (m, 1H), 4.34-4.31 (m, 1H), 4.24-4.21 (m, 1H), 3.73 (m, 4H), 3.33 (s, 3H), 2.86-2.80 (m, 3H), 2.72-2.67 (m, 2H), 2.58-2.52 (m, 4H), 2.26-2.24 (m, 1H). LCMS R_(T)=0.651 min, m/z=479.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.651 min, ESI+ found [M+H]=479.2.

SFC condition: Column: Chiralcel (OD-3 100×4.6 mm I.D., 3 um) Mobile phase: A:CO2 B:ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min, Column temperature:40° C.

Example 753

1-[(2-fluorophenyl)methyl]-N-[(6S)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 199. The racemic material was separated by chiral SFC to afford:

1-[(2-fluorophenyl)methyl]-N-[(6 S)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.621 min) (17.4 mg, 24%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.41-7.38 m, 2H), 7.22-7.15 (m, 2H), 6.19 (s, 1H), 5.55 (s, 2H), 4.55-4.50 (m, 1H), 4.33-4.31 (m, 1H), 4.23-4.21 (m, 1H), 3.73-3.71 (m, 4H), 3.33 (s, 3H), 2.86-2.81 (m, 3H), 2.72-2.67 (m, 2H), 2.58-2.52 (m, 4H), 2.26-2.23 (m, 1H). LCMS R_(T)=0.668 min, m/z=497.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.668 min, ESI+ found [M+H]=497.2.

1-[(2-fluorophenyl)methyl]-N-[(6R)-4-methyl-2-(2-morpholinoethyl)-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 6.349 min) (19.8 mg, 27%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.42-7.38 (m, 2H), 7.22-7.15 (m, 2H), 6.19 (s, 1H), 5.55 (s, 2H), 4.54-4.52 (m, 1H), 4.33-4.30 (m, 1H), 4.24-4.21 (m, 1H), 3.73-3.70 (m, 4H), 3.33 (s, 3H), 2.86-2.81 (m, 3H), 2.72-2.68 (m, 2H), 2.58-2.52 (m, 4H), 2.26-2.24 (m, 1H). LCMS R_(T)=0.665 min, m/z=497.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.665 min, ESI+ found [M+H]=497.2.

SFC condition: Column: Chiralcel (OD-3 100×4.6 mm I.D., 3 um) Mobile phase: A:CO2 B:ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min, Column temperature: 40° C.

Example 754 WX Method 213

1-benzyl-N-[(6S)-2-(azetidin-3-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide hydrochloride and 1-benzyl-N-[(6R)-2-(azetidin-3-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide hydrochloride

To a stirred mixture solution of tert-butyl 3-[6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate (60 mg, 0.12 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (120 mg, 1.05 mmol). The resulting mixture was stirred at 25° C. for 12 h and then quenched by addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 5-35%/0.05% HCl in water) to afford

N-[2-(azetidin-3-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1-benzyl-1,2,4-triazole-3-carboxamide (35 mg, 41%) as a white solid.

The racemic material was separated by chiral SFC and then purified by RP-HPLC (acetonitrile 5-35%/0.05% HCl in water) to give:

1-benzyl-N-[(6S)-2-(azetidin-3-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide hydrochloride (Peak 1, retention time 2.254 min) (11.0 mg, 31%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.41-7.30 (m, 5H), 6.36 (s, 1H), 5.52 (s, 2H), 4.53-4.50 (m, 1H), 4.47-4.14 (m, 7H), 3.34 (s, 3H), 2.88-2.78 (m, 1H), 2.35-2.27 (m, 1H). LCMS R_(T)=2.187 min; m/z=421.2 (M+H)⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 2.187 min, ESI+ found [M+H]=421.2.

1-benzyl-N-[(6R)-2-(azetidin-3-yl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide hydrochloride (Peak 2 retention time 3.065 min) (11.1 mg, 32%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 7.43-7.30 (m, 5H), 6.37 (s, 1H), 5.53 (s, 2H), 4.55-4.50 (m, 1H), 4.48-4.14 (m, 7H), 3.37 (s, 3H), 2.89-2.78 (m, 1H), 2.37-2.29 (m, 1H).

LCMS R_(T)=2.195 min; m/z=421.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 2.195 min, ESI+ found [M+H]=421.2.

SFC conditions: Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um Mobile phase: 40% of methanol (0.1% ethanolamine) in CO₂. Flow rate: 2.5 mL/min. Column temp: 35° C.

Example 755 WX Method 192

1-benzyl-N-[(6S)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: (2-methoxyethoxy)ethane

A mixture of iodomethane (7.7 mL, 124.0 mmol), ethylene glycol monovinyl ether (5.0 g, 56.8 mmol) and potassium hydroxide (3.8 g, 68.1 mmol) was stirred at 0° C. for 30 min and then at 20° C. for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude (2-methoxyethoxy)ethane (2 g, 35%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 6.52-6.47 (m, 1H), 4.19-4.02 (m, 1H), 4.01-3.99 (m, 1H), 3.82 (t, J=4.4 Hz, 2H), 3.62 (t, J=2.4 Hz, 2H), 3.37 (s, 3H).

Step 2: (E)-tert-butyl (2-(2-(2-methoxyethoxy)vinyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of tert-butyl N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (500 mg, 1.39 mmol), N,N-diisopropylethylamine (540 mg, 4.18 mmol), 1-methoxy-2-vinyloxy-ethane (142 mg, 1.39 mmol) and bis(tri-tert-butylphosphine)palladium(0) (71 mg, 0.14 mmol) in 1,4-dioxane (15 mL) was heated at 80° C. for 12 h under nitrogen protection. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford (E)-tert-butyl (2-(2-(2-methoxyethoxy)vinyl)-4-methyl-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]di azepin-6-yl)carbamate (140 mg, 26%) as a yellow solid, used as is in the next step. LC-MS R_(T)=1.535 min, m/z=381.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.535 min, ESI+ found [M+H]=381.2.

Step 3: tert-butyl (2-(2-(2-methoxyethoxy)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of (E)-tert-butyl (2-(2-(2-methoxyethoxy)vinyl)-4-methyl-5-oxo-5,6, 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (140 mg, 0.37 mmol) and palladium on carbon (10%, 0.1 g) in methanol (10 mL) was hydrogenated (50 psi) at 25° C. for 1.5 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford tert-butyl (2-(2-(2-methoxyethoxy)ethyl)-4-methyl-5-oxo-5, 6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]di azepin-6-yl)carbamate (140 mg, 99%) as a colorless oil. LC-MS R_(T)=1.39 min, m/z=383.2 [M+H]+. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.39 min, ESI+ found [M+H]=383.2.

Step 4: 6-amino-2-(2-(2-methoxyethoxy)ethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a stirred mixture solution of tert-butyl (2-(2-(2-methoxyethoxy)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]di azepin-6-yl)carbamate (110 mg, 0.29 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (656 mg, 5.75 mmol). The resulting mixture was stirred 12 h at 25° C. and then quenched by addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduce pressure to afford the crude 6-amino-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (80 mg, 98%) as a yellow oil. LC-MS R_(T)=1.256 min, m/z=283.2 [M+H]+.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.256 min, ESI+ found [M+H]=283.2.

Step 5: 1-benzyl-N-[(6S)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (17 mg, 0.09 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (27 mg, 0.14 mmol), 6-amino-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.07 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20° C. for 12 h. The mixture was concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 25-45%/0.05% NH₃.H₂O in water) to afford 1-benzyl-N-[2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (20 mg, 60%) as a white solid. The racemic material was further separated by chiral SFC to give:

1-benzyl-N-[(6S)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.593 min) (6 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 7.30-7.22 (m, 5H), 6.11 (s, 1H), 5.37 (s, 2H), 4.44-4.40 (m, 1H), 4.27-4.20 (m, 1H), 4.16-4.07 (m, 1H), 3.65 (t, J=6.8 Hz, 2H), 3.54-3.51 (m, 2H), 3.46-3.42 (m, 2H), 3.25 (s, 3H), 3.23 (s, 3H), 2.79-2.71 (m, 3H), 2.16-2.13 (m, 1H). LC-MS R_(T)=1.355 min, m/z=468.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.355 min, ESI+ found [M+H]=468.2.

1-benzyl-N-[(6R)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.435 min) (2 mg, 10%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 7.30-7.23 (m, 5H), 6.11 (s, 1H), 5.38 (s, 2H), 4.44-4.40 (m, 1H), 4.27-4.20 (m, 1H), 4.16-4.07 (m, 1H), 3.65 (t, J=6.8 Hz, 2H), 3.54-3.51 (m, 2H), 3.46-3.42 (m, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.79-2.73 (m, 3H), 2.18-2.14 (m, 1H). LC-MS R_(T)=1.400 min, m/z=468.2 [M+H]+. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.400 min, ESI+ found [M+H]=468.2.

SFC condition: column: chiralcel OD-3 100×4.6 mm I.D., 3 um mobile phase: A:CO₂; B: ethanol (0.05% DEA) gradient: hold 5% for 1.0 min, then from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1.0 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example 756 WX Method 198

1-benzyl-N-[(6S)-2-[2-(azetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(azetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl (2-(2-(azetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

To a solution of azetidine hydrochloride (186 mg, 1.99 mmol) in acetonitrile (5 mL) was added potassium carbonate (549 mg, 3.98 mmol). The mixture was stirred at 25° C. for 3 h. Then the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was added to a mixture of 2-(6-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)ethyl methanesulfonate (160 mg, 0.40 mmol), N,N-diisopropylethylamine (308 mg, 2.39 mmol) and sodium iodide (60 mg, 0.40 mmol) in N,N-dimethylformamide (4 mL). The mixture was heated at 50° C. for 16 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford tert-butyl (2-(2-(azetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (110 mg, 76%) as a yellow solid, used as is in the next step.

Step 2: 6-amino-2-(2-(azetidin-1-yl)ethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride

To a solution of tert-butyl (2-(2-(azetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (110 mg, 0.30 mmol) in ethyl acetate (20 mL) was added hydrochloric acid (4M in ethyl acetate, 12.0 mL, 48.0 mmol. The reaction mixture was stirred at 25° C. for 15 h and concentrated under reduced pressure to afford crude 6-amino-2-(2-(azetidin-1-yl)ethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride (90 mg, 99%) as a white solid, used in the next step without further purification.

Step 3: 1-benzyl-N-[(6S)-2-[2-(azetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(azetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2-(2-(azetidin-1-yl)ethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride (60 mg, 0.20 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (41 mg, 0.20 mmol), 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (58 mg, 0.30 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15° C. for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (3-33% acetonitrile in water and 0.05% hydrochloric acid) to afford N-(2-(2-(azetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1-benzyl-1H-1,2,4-triazole-3-carboxamide (40 mg, 45%) as a white solid. The racemic compound was further separated by chiral SFC to afford:

1-benzyl-N-[(6S)-2-[2-(azetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.941 min) (4.2 mg, 5%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.39-7.31 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.57-4.52 (m, 1H), 4.33-4.31 (m, 1H), 4.24-4.21 (m, 1H), 3.36-3.34 (m, 2H), 3.33 (s, 3H), 3.32-3.30 (m, 2H), 2.87-2.78 (m, 3H), 2.67-2.63 (m, 2H), 2.25-2.22 (m, 1H), 2.15-2.10 (m, 2H). LC-MS R_(T)=0.603 min, m/z=449.1 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.603 min, ESI+ found [M+H]=449.1.

1-benzyl-N-[(6R)-2-[2-(azetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.372 min) (4.1 mg, 5%) as a white solid. ¹H NMR (400 MHz, CD30D) δ 8.57 (s, 1H), 7.40-7.32 (m, 5H), 6.16 (s, 1H), 5.47 (s, 2H), 4.57-4.51 (m, 1H), 4.33-4.31 (m, 1H), 4.25-4.16 (m, 1H), 3.33 (s, 3H), 3.32-3.30 (m, 2H), 3.29-3.28 (m, 2H), 2.87-2.82 (m, 1H), 2.77 (t, J=8.0 Hz, 2H), 2.66-2.61 (m, 2H), 2.29-2.21 (m, 1H), 2.16-2.08 (m, 2H). LC-MS R_(T)=0.604 min, m/z=449.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.604 min, ESI+ found [M+H]=449.1.

SFC condition: column chiralpak AD-3 (100 mm*4.6 mm I.D), 3 um mobile phase: A:CO2; B: EtOH (0.05% DEA) gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min, Column temperature: 40° C.

Example 757 WX Method 194

1-benzyl-N-[(6S)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl (2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

To a solution of 6-amino-2-bromo-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (9.0 g, 34.7 mmol) in dichloromethane (10 mL) was added triethylamine (14.5 mL, 104.2 mmol) and di-tert-butyldicarbonate (11.4 g, 52.1 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 16 h and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford tert-butyl (2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamat e (10.5 g, 84%) as a white solid, used as is in the next step.

Step 2: tert-butyl (4-methyl-5-oxo-2-vinyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of tert-butyl (2-bromo-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (6.0 g, 16.70 mmol), cesium fluoride (7.6 g, 50.11 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.2 g, 1.67 mmol) and potassium vinyltrifluoroborate (4.5 g, 33.40 mmol) in 1,4-dioxane (100 mL)/water (10 mL) was heated at 90° C. for 16 h under nitrogen protection. After cooled, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford tert-butyl (4-methyl-5-oxo-2-vinyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (4.2 g, 82%) as a yellow solid, used as is in the next step. LC-MS R_(T)=0.687 min, m/z=250.8 [M−56]⁺

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.687 min, ESI+ found [M−56]=250.8.

Step 3: tert-butyl (4-methyl-2-(oxiran-2-yl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

To a solution of tert-butyl (4-methyl-5-oxo-2-vinyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (3.7 g, 12.08 mmol) in dichloromethane (15 mL) was added 3-chloroperoxybenzoicacid (2.1 g, 12.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then quenched by addition of saturated aqueous sodium thiosulfate (5 mL). The organic layer was separated, washed with brine (5 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford tert-butyl (4-methyl-2-(oxiran-2-yl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (1.1 g, 28%) as a colorless solid. LC-MS R_(T)=0.704 min, m/z=266.8 [M−56]+.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.704 min, ESI+ found [M−56]=266.8.

Step 4: tert-butyl (2-(2-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of tert-butyl (4-methyl-2-(oxiran-2-yl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (1.6 g, 4.96 mmol), palladium on carbon (10%, 528 mg) and ammonium formate (3.2 g, 49.63 mmol) in methanol (15 mL) was hydrogenated (15 psi) at 20° C. for 16 h and then filtered. The filtrate was concentrated under reduced pressure to give crude tert-butyl (2-(2-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (1.4 g, 87%) as a white solid. LC-MS R_(T)=0.704 min, m/z=268.9 [M−56]+. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.704 min, ESI+ found [M−56]=268.9.

Step 5: 2-(6-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)ethyl methanesulfonate

To a solution of tert-butyl (2-(2-hydroxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (600 mg, 1.85 mmol) in dichloromethane (20 mL) was added triethylamine (0.77 mL, 5.55 mmol) and methanesulfonyl chloride (600 mg, 5.24 mmol). The reaction mixture was stirred at 20° C. for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 80% ethyl acetate in petroleum ether) to afford 2-(6-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)ethyl methanesulfonate (632 mg, 85%) as a white solid, used as is in the next step.

Step 6: tert-butyl (2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

To a solution of 3-methoxyazetidinehydrochloride (246 mg, 1.99 mmol) in acetonitrile (5 mL) was added potassium carbonate (549 mg, 3.98 mmol). The mixture was stirred at 25° C. for 3 h and filtered. The filtrate was concentrated under reduced pressure. The residue was added to a mixture of 2-(6-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)ethyl methanesulfonate (160 mg, 0.40 mmol), N,N-diisopropylethylamine (54 mg, 0.40 mmol) and sodium iodide (60 mg, 0.40 mmol) in N,N-dimethylformamide (4 mL) was heated at 50° C. for 16 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give tert-butyl (2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (150 mg, 96%) as a yellow solid, used as is in the next step. LC-MS R_(T)=0.551 min, m/z=394.0 [M−56]+. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.551 min, ESI+ found [M−56]=394.0.

Step 7: 6-amino-2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride

To a solution of tert-butyl (2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (150 mg, 0.38 mmol) in ethyl acetate (20 mL) was added hydrochloric acid (4 M in ethyl acetate, 15.0 mL, 60.0 mmol). The reaction mixture was stirred at 25° C. for 15 h and concentrated under reduced pressure to give crude 6-amino-2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride (125 mg, 99%) as a white solid, used in the next step without further purification.

Step 8: 1-benzyl-N-[(6S)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 6-amino-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one hydrochloride (80 mg, 0.24 mmol), 1-benzyl-1,2,4-triazole-3-carboxylic acid (49 mg, 0.24 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (70 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15° C. for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by RP-HPLC (5-35% acetonitrile in water and 0.05% hydrochloric acid) to afford 1-benzyl-N-(2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 34%) as a white solid. The racemic compound was further separated by chiral SFC to afford:

1-benzyl-N-[(6 S)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 1.696 min) (3.5 mg, 3%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.35 (s, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.57-4.52 (m, 1H), 4.37-4.31 (m, 1H), 4.26-4.19 (m, 1H), 4.06-4.00 (m, 1H), 3.63 (t, J=6.8 Hz, 2H), 3.33 (s, 3H), 3.25 (s, 3H), 3.02 (t, J=6.4 Hz, 2H), 2.84-2.80 (m, 3H), 2.67 (t, J=7.2 Hz, 2H), 2.29-2.21 (m, 1H). LC-MS R_(T)=0.556 min, m/z=479.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 min) retention time 0.556 min, ESI+ found [M+H]=479.1. 1-benzyl-N-[(6R)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 1.995 min) (3.5 mg, 3%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.38-7.32 (m, 5H), 6.17 (s, 1H), 5.47 (s, 2H), 4.57-4.52 (m, 1H), 4.36-4.31 (m, 1H), 4.26-4.17 (m, 1H), 4.06-4.02 (m, 1H), 3.63 (t, J=7.0 Hz, 2H), 3.33 (s, 3H), 3.25 (s, 3H), 3.02 (t, J=6.6 Hz, 2H), 2.84-2.80 (m, 3H), 2.67 (t, J=7.4 Hz, 2H), 2.29-2.21 (m, 1H). LC-MS R_(T)=0.550 min, m/z=479.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.550 min, ESI+ found [M+H]=479.1.

SFC condition: column chiralpak AD-3 (50 mm*4.6 mm I.D), 3 um mobile phase: A:CO2; B: EtOH (0.05% DEA) gradient: hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min. Flow rate: 4 mL/min. Column temperature: 40° C.

Example 758 WX Method 190

1-benzyl-N-[(6S)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl N-[2-[(E)-2-ethoxyvinyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate

A mixture of ethyl vinyl ether (40 mg, 0.56 mmol), N,N-diisopropylethylamine (216 mg, 1.67 mmol), bis(tri-tert-butylphosphine)palladium (28 mg, 0.06 mmol) and tert-butyl N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl) carbamate (200 mg, 0.56 mmol) in 1,4-dioxane (15 mL) was heated at 80° C. for 12 h under nitrogen protection. After cooled, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford tert-butyl N-[2-[(E)-2-ethoxyvinyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (100 mg, 51%) as a yellow solid. LCMS R_(T)=2.13 min, m/z=351.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 2.13 min, ESI+ found [M+H]=351.2.

Step 2: tert-butyl (2-(2-ethoxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of tert-butyl N-[2-[(E)-2-ethoxyvinyl]-4-methyl-5-oxo-7,8-d8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (100 mg, 0.29 mmol) and palladium on carbon (10%, 0.1 g) in methanol (50 mL) was hydrogenated (50 psi) at 25° C. for 1.5 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to give tert-butyl (2-(2-ethoxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) carbamate (60 mg, 60%) as a yellow oil. LCMS R_(T)=0.779 min, m/z=353.1 [M+H].

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.779 min, ESI+ found [M+H]=353.1.

Step 3: 6-amino-2-(2-ethoxyethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of tert-butyl (2-(2-ethoxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl) carbamate (90 mg, 0.26 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (874 mg, 7.66 mmol). The resulting mixture was stirred at 25° C. for 12 h and then quenched by addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduce pressure to give the crude 6-amino-2-(2-ethoxyethyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (50 mg, 78%) as a yellow oil, used in the next step without further purification.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.325 min, ESI+ found [M+H]=253.2.

Step 4: 1-benzyl-N-[(6S)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (24 mg, 0.12 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (38 mg, 0.20 mmol), 6-amino-2-(2-ethoxyethyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (25 mg, 0.10 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20° C. for 12 h. The mixture was concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 22-52%/0.05% NH₃.H₂O in water) to afford 1-benzyl-N-[2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (25 mg, 58%) as a white solid. The racemic material was further separated by chiral SFC to give:

1-benzyl-N-[(6S)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.421 min) (4.3 mg, 17%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 7.27-7.24 (m, 5H), 6.09 (s, 1H), 5.38 (s, 2H), 4.44-4.41 (m, 1H), 4.36-4.30 (m, 1H), 4.24-4.19 (m, 1H), 3.61 (t, J=6.8 Hz, 2H), 3.45-3.43 (m, 2H), 3.23 (s, 3H), 2.78-2.74 (m, 3H), 2.17-2.13 (m, 1H), 1.09 (t, J=7.2 Hz, 3H). LC-MS RT=1.482 min, m/z=438.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.482 min, ESI+ found [M+H]=438.2.

1-benzyl-N-[(6R)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.225 min) (7.5 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 7.27-7.24 (m, 5H), 6.09 (s, 1H), 5.38 (s, 2H), 4.44-4.41 (m, 1H), 4.30-4.20 (m, 1H), 4.19-4.10 (m, 1H), 3.61 (t, J=6.8 Hz, 2H), 3.45-3.43 (m, 2H), 3.23 (s, 3H), 2.78-2.74 (m, 3H), 2.19-2.13 (m, 1H), 1.09 (t, J=7.2 Hz, 3H). LC-MS RT=1.483 min, m/z=438.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.483 min, ESI+ found [M+H]=438.2.

SFC condition: column: chiralcel OD-3 50×4.6 mm I.D., 3 um mobile phase: A:CO₂; B: ethanol (0.05% DEA) gradient: hold 5% for 0.2 min, then from 5% to 40% of Bin 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example 759 WX Method 212

tert-butyl 3-[(6S)-6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate and tert-butyl 3-[(6R)-6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate

Step 1: (6-(1-benzyl-1H-1,2,4-triazole-3-carboxamido)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-2-yl)boronic acid

A mixture of 1-benzyl-N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide (2.5 g, 5.63 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.1 g, 8.44 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium dichloride (0.4 g, 0.56 mmol) and potassium acetate (1.7 g, 16.88 mmol) in 1,4-dioxane (20 mL) was heated at 90° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 18-28/0.05% ammonia in water) to give [6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]boronic acid (1.0 g, 43%) as a white solid. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.687 min, ESI+ found [M+H]=410.1.

Step 2: tert-butyl 3-[(6S)-6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate and tert-butyl 3-[(6R)-6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate

A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (276 mg, 0.98 mmol), [6-[(1-benzyl-,2,4-triazole-3-carbonyl)amino]-4-methyl-1-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]boronic acid (200 mg, 0.49 mmol), cesium carbonate (159 mg, 0.49 mmol) and cyclopentyl(diphenyl)phosphane dichloromethane dichloropalladium iron (399 mg, 0.49 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 90° C. for 0.5 h under microwave conditions. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford tert-butyl 3-[6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate (60 mg, 24%) as a white solid. The racemic material (25 mg) was further separated by chiral SFC to give:

tert-butyl 3-[(6S)-6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate (Peak 1 retention time 5.537 min) (7.5 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.41-7.31 (m, 5H), 6.30 (s, 1H), 5.47 (s, 2H), 4.58-4.49 (m, 1H), 4.44-4.19 (m, 4H), 4.09-3.98 (m, 2H), 3.85-3.76 (m, 1H), 3.39 (s, 3H), 2.92-2.79 (m, 1H), 2.32-2.22 (s, 1H), 1.46 (s, 9H). LCMS R_(T)=1.747 min; m/z=421.2 (M−100)⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 1.747 min, ESI+ found [M−100]=421.2. tert-butyl 3-[(6R)-6-[(1-benzyl-1,2,4-triazole-3-carbonyl)amino]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]azetidine-1-carboxylate (Peak 2 retention time 6.650 min) (10.0 mg, 40%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.41-7.31 (m, 5H), 6.30 (s, 1H), 5.47 (s, 2H), 4.58-4.48 (m, 1H), 4.45-4.19 (m, 4H), 4.09-3.98 (m, 2H), 3.85-3.76 (m, 1H), 3.39 (s, 3H), 2.92-2.79 (m, 1H), 2.32-2.22 (s, 1H), 1.46 (s, 9H). LCMS R_(T)=1.747 min; m/z=421.2 (M−100)⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 1.747 min, ESI+ found [M−100]=421.2.

SFC condition Column: ChiralPak AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:Ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min. Flow rate: 2.5 mL/min. Column temperature:40° C.

Example 760

1-[(2-fluorophenyl)methyl]-N-[(6S)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-di hydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-di hydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 192. The racemic material was separated by chiral SFC to afford:

1-[(2-fluorophenyl)methyl]-N-[(6S)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.167 min) (17 mg, 56%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 7.30-7.26 (m, 2H), 7.11-7.02 (m, 2H), 6.11 (s, 1H), 5.45 (s, 2H), 4.43-4.40 (m, 1H), 4.25-4.22 (m, 1H), 4.15-4.10 (m, 1H), 3.64 (t, J=6.8 Hz, 2H), 3.52-3.51 (m, 2H), 3.49-3.45 (m, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 2.78-2.75 (m, 3H), 2.19-2.14 (m, 1H). LC-MS R_(T)=0.748 min, m/z=508.2.2 [M+Na]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.748 min, ESI+ found [M+Na]=508.2.

1-[(2-fluorophenyl)methyl]-N-[(6R)-2-[2-(2-methoxyethoxy)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.878 min) (11.4 mg, 38%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 7.30-7.26 (m, 2H), 7.11-7.02 (m, 2H), 6.11 (s, 1H), 5.45 (s, 2H), 4.43-4.40 (m, 1H), 4.26-4.22 (m, 1H), 4.16-4.10 (m, 1H), 3.64 (t, J=6.8 Hz, 2H), 3.52-3.51 (m, 2H), 3.49-3.44 (m, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 2.78-2.75 (m, 3H), 2.19-2.14 (m, 1H). LC-MS R_(T)=0.744 min, m/z=508.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.744 min, ESI+ found [M+Na]=508.2.

SFC conditions: (Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% dethyl acetate), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 761 WX Method 203

1-benzyl-N-[(6S)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-di hydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl (2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of 2-[6-(tert-butoxycarbonylamino)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]ethyl methanesulfonate (230 mg, 0.57 mmol), 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (232 mg, 1.71 mmol) and potassium carbonate (237 mg, 1.71 mmol) in N,N-dimethylformamide (10 mL) was heated at 50° C. for 6 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 25-55%/0.05% NH₄OH in water) to afford tert-butyl (2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (100 mg, 43%) as a colorless oil, used as is in the next step.

Step 2: 2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride

To a solution of tert-butyl (2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (100 mg, 0.25 mmol) in ethyl acetate (5 mL) was added hydrochloric acid (4 M in ethyl acetate, 4.0 mL, 16.0 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated under reduced pressure to afford crude 2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-6-amino-4-methyl-7,8-dihydro-4H-pyrazol o[1,5-a][1,3]diazepin-5(6H)-one hydrochloride (80 mg, 95%) as a white solid, used in the next step without further purification.

Step 3: 1-benzyl-N-[(6S)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-di hydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (30 mg, 0.15 mmol), 2-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-6-amino-4-methyl-7,8-dihydro-4H-pyrazol o[1,5-a][1,3]diazepin-5(6H)-one hydrochloride (40 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (23 mg, 0.12 mmol) and 1-hydroxybenzotriazole (16 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 18-48%/0.05% NH₄OH in water) to afford 1-benzyl-N-[4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (30 mg, 52%) as a white solid. The racemic material was separated by chiral SFC to give:

1-benzyl-N-[(6S)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peaks 1 and 2, retention time 5.386 min, 5.502 min) (10.7 mg, 36%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.39-7.33 (m, 5H), 6.20 (s, 1H), 5.47 (s, 2H), 4.55-4.52 (m, 1H), 4.33-4.31 (m, 1H), 4.30-4.25 (m, 1H), 4.24-4.15 (m, 1H), 4.06-4.03 (m, 1H), 3.64-3.61 (m, 2H), 3.33 (s, 3H), 2.93-2.77 (m, 6H), 2.62-2.59 (m, 1H), 2.26-2.20 (m, 1H), 1.92-1.89 (m, 1H), 1.78-1.75 (m, 1H). LCMS R_(T)=0.670 min, m/z=491.2 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.670 min, ESI+ found [M+H]=491.2.

1-benzyl-N-[(6R)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (peak 3, retention time 6.674 min) (9.8 mg, 33%) as a white solid. ¹H NMR (400 MHz, CD₃OD) 8.57 (s, 1H), 7.39-7.33 (m, 5H), 6.20 (s, 1H), 5.47 (s, 2H), 4.55-4.52 (m, 1H), 4.34-4.30 (m, 1H), 4.30-4.24 (m, 1H), 4.25-4.15 (m, 1H), 4.06-4.03 (m, 1H), 3.64-3.61 (m, 2H), 3.33 (s, 3H), 2.93-2.77 (m, 6H), 2.62-2.59 (m, 1H), 2.26-2.20 (m, 1H), 1.92-1.89 (m, 1H), 1.78-1.74 (m, 1H).

LCMS R_(T)=0.669 min, m/z=491.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.669 min, ESI+ found [M+H]=491.2.

SFC condition: Column: Chiralcel (OD-3 100×4.6 mm I.D., 3 um) Mobile phase: A:CO2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature:40° C.

Example 762

1-[(2-fluorophenyl)methyl]-N-[(6S)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 203. The racemic material was separated by chiral SFC to afford:

1-[(2-fluorophenyl)methyl]-N-[(6 S)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peaks 1 and 2, retention time 4.939, 5.026 min) (15.5 mg, 39%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.41-7.36 (m, 2H), 7.21-7.14 (m, 2H), 6.20 (s, 1H), 5.47 (s, 2H), 4.55-4.52 (m, 1H), 4.33-4.31 (m, 1H), 4.30-4.25 (m, 1H), 4.24-4.15 (m, 1H), 4.06-4.03 (m, 1H), 3.64-3.61 (m, 2H), 3.33 (s, 3H), 2.93-2.77 (m, 6H), 2.62-2.59 (m, 1H), 2.26-2.20 (m, 1H), 1.92-1.89 (m, 1H), 1.78-1.75 (m, 1H). LCMS R_(T)=0.680 min, m/z=509.2 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.05% ammonium hydroxide over 1.5 mins) retention time 0.680 min, ESI+ found [M+H]=509.2.

1-[(2-fluorophenyl)methyl]-N-[(6 S)-4-methyl-2-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peaks 3, retention time 5.812 min) (13.9 mg, 35%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.41-7.36 (m, 2H), 7.21-7.14 (m, 2H), 6.20 (s, 1H), 5.55 (s, 2H), 4.55-4.52 (m, 1H), 4.33-4.31 (m, 1H), 4.30-4.25 (m, 1H), 4.24-4.15 (m, 1H), 4.06-4.03 (m, 1H), 3.64-3.61 (m, 2H), 3.33 (s, 3H), 2.93-2.77 (m, 6H), 2.62-2.59 (m, 1H), 2.26-2.20 (m, 1H), 1.92-1.89 (m, 1H), 1.78-1.75 (m, 1H). LCMS R_(T)=0.685 min, m/z=509.2 [M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.685 min, ESI+ found [M+H]=509.2.

SFC condition: Column: Chiralcel (OD-3 100×4.6 mm I.D., 3 um) Mobile phase: A:CO2 B:ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 763

1-[(2-fluorophenyl)methyl]-N-[(6S)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 190. The racemic material was separated by chiral SFC to afford:

1-[(2-fluorophenyl)methyl]-N-[(6S)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.003 min) (6.8 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 7.34-7.22 (m, 2H), 7.12-7.00 (m, 2H), 6.08 (s, 1H), 5.45 (s, 2H), 4.45-4.40 (m, 1H), 4.27-4.19 (m, 1H), 4.16-4.07 (m, 1H), 3.60 (t, J=6.8 Hz, 2H), 3.43 (q, J=6.8 Hz, 2H), 3.23 (s, 3H), 2.78-2.70 (m, 3H), 2.19-2.11 (m, 1H), 1.08 (t, J=7.2 Hz, 3H). LC-MS RT=0.760 min, m/z=456.1 [M+H]⁺. LCMS (5 to 95%5% acetonitrile in water+0.030.03% trifluoacetic acid over 1.5 mins) retention time 0.760 min, ESI+ found [M+H]=456.1.

1-[(2-fluorophenyl)methyl]-N-[1-(6R)-2-(2-ethoxyethyl)-4-methyl-5-oxo-7,8-dihydro-H-pyrazolo[[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.673 mn) for 2.5 (9.5 mg, 360) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 7.33-7.22 (m, 2H), 7.13-7.00 (m, 2H), 6.08 (s, 1H), 5.45 (s, 2H), 4.44-4.40 (m, 1H), 4.27-4.19 (m, 1H), 4.16-4.07 (m, 1H), 3.60 (t, J=6.8 Hz, 2H), 3.43 (q, J=6.8 Hz, 2H), 3.23 (s, 3H), 2.78-2.70 (min, 3H), 2.19%-2.11 (m, for 1H), 1.09 (t, J=7.2 Hz, 3H). LC-MS RT=0.760 min. m/z=456.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.760 min, ESI+ found [M+H]=456.1.

SFC condition: (Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% dethyl acetate), Gradient: from 50 to 40% of B in 4.5 min and hold 40% for 2.5 min, then 50 of B for 1.0 min, Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 764 WX Method 209

(1S)-1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-6-carboxamide

A mixture of 1-hydroxybenzotriazole (35 mg, 0.26 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (374 mg, 1.95 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (250 mg, 1.30 mmol) and (1S)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (270 mg, 1.30 mmol) in N,N-dimethylformamide (10 mL) was stirred at 15° C. for 12 h and poured into ice water (50 mL). The resulting solid was collected by filtration and dried under reduced pressure to give (1 S)-1-ethyl-I-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-6-carboxamide (406 mg, 82%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J=7.6 Hz, 1H), 8.64 (s, 1H), 7.88 (s, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.36-7.24 (m, 3H), 5.15 (s, 2H), 4.91-4.85 (m, 1H), 4.59-4.46 (m, 2H), 3.35-3.34 (m, 3H), 1.87-1.73 (m, 2H), 1.40 (s, 3H), 0.68 (t, J=7.2 Hz, 3H). LCMS R_(T)=0.841 min; m/z=382.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.841 min, ESI+ found [M+H]=382.1.

Chiral HPLC retention time: 3.978 min (Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um. Mobile phase: A: CO2 B:ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40° C.)

Example 765 WX Method 208

(1R)-1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-6-carboxamide

A mixture of 1-hydroxybenzotriazole (35 mg, 0.26 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (374 mg, 1.95 mmol), (3S)-3-amino-5-methyl-2,3-dihydro-1,5-benzoxazepin-4-one (250 mg, 1.30 mmol) and (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid (270 mg, 1.30 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 12 h and poured into ice water (100 mL). The resulting solid was collected by filtration and dried under reduced pressure to give (1R)-1-ethyl-1-methyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-3H-furo[3,4-c]pyridine-6-carboxamide (404 mg, 81%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.85 (s, 1H), 7.45-7.42 (m, 1H), 7.33-7.31 (m, 2H), 7.30-7.23 (m, 1H), 5.16 (s, 2H), 5.15-5.12 (m, 1H), 4.66-4.62 (m, 1H), 4.42-4.37 (m, 1H), 3.42 (s, 3H), 1.87-1.82 (m, 2H), 1.45 (s, 3H), 0.76 (t, J=7.6 Hz, 3H). LCMS R_(T)=0.850 min; m/z=382.1 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 1.5 mins) retention time 0.850 min, ESI+ found [M+H]=382.1.

Chiral HPLC retention time: 3.478 min (Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um. Mobile phase: A:CO2 B:ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40° C.

Example 766 WX Method 207

1-benzyl-N-[(6S)-2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: 6-amino-2-(2-hydroxyethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a solution of tert-butyl N-[2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (200 mg, 0.62 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (703 mg, 6.17 mmol). The reaction mixture was stirred at 20° C. for 3 h and concentrated under reduced pressure. The residue was dissolved in acetonitrile (10 mL), added potassium carbonate (1.38 g, 10 mmol) and stirred for 30 min. The solid was removed by filtration and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 50% methanol in dichloromethane) to afford 6-amino-2-(2-hydroxyethyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (120 mg, 87%) as a yellow oil, used as is in the next step.

Step 2: 1-benzyl-N-[(6S)-2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (63 mg, 0.31 mmol), 6-amino-2-(2-hydroxyethyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (70 mg, 0.31 mmol), 1-hydroxybenzotriazole (42 mg, 0.31 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (60 mg, 0.31 mmol) in N,N-dimethylformamide (6 mL) was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 10-40/0.05% HCl in water) to afford 1-benzyl-N-[2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (30 mg, 24%) as a white solid. The racemic material was further separated by chiral SFC to give:

1-benzyl-N-[(6S)-2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.640 min) (11.5 mg, 38%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.41-7.29 (m, 5H), 6.19 (s, 1H), 5.48 (s, 2H), 4.58-4.53 (m, 1H), 4.39-4.31 (m, 1H), 4.28-4.17 (m, 1H), 3.82 (t, J=6.8 Hz, 2H), 3.35-3.33 (m, 3H), 2.92-2.77 (m, 3H), 2.29-2.21 (m, 1H). LCMS R_(T)=0.992 min; m/z=410.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% formic acid over 2.0 mins) retention time 0.992 min, ESI+ found [M+H]=410.2.

1-benzyl-N-[(6R)-2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.416 min) (10.2 mg, 33%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.41-7.29 (m, 5H), 6.19 (s, 1H), 5.47 (s, 2H), 4.58-4.53 (m, 1H), 4.39-4.31 (m, 1H), 4.28-4.17 (m, 1H), 3.82 (t, J=6.8 Hz, 2H), 3.37-3.33 (m, 3H), 2.92-2.76 (m, 3H), 2.29-2.20 (m, 1H). LCMS R_(T)=0.992 min; m/z=410.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% formic acid over 2.0 mins) retention time 0.992 min, ESI+ found [M+H]=410.2.

SFC condition: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 umMobile phase: A:CO₂ B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature:40° C.

Example 767 WX Method 196

1-benzyl-N-[(6S)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl (2-(2-methoxyethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of tert-butyl N-[2-(2-hydroxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (250 mg, 0.77 mmol), iodomethane (2 mL, 32.13 mmol) and silver(II) oxide (893 mg, 3.85 mmol) was stirred at 20° C. for 14 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate in petroleum ether) to afford tert-butyl N-[2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (200 mg, 77%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 5.93 (s, 1H), 5.39 (d, J=7.8 Hz, 1H), 4.36-4.23 (m, 2H), 4.07-3.98 (m, 1H), 3.65-3.61 (m, 2H), 3.37 (s, 3H), 3.30 (s, 3H), 2.94-2.87 (m, 1H), 2.84 (d, J=8.0 Hz, 2H), 1.94-1.86 (m, 1H), 1.39 (s, 9H). LC-MS R_(T)=0.653 min, m/z=338.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.653 min, ESI+ found [M+H]=338.9.

Step 2: 6-amino-2-(2-methoxyethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a stirred mixture solution of tert-butyl N-[2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]carbamate (200 mg, 0.59 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL, 5.91 mmol). The resulting mixture was stirred 12 h at 25° C. and then quenched by addition of saturated aqueous sodium bicarbonate (10 mL). The resulting mixture was extracted with dichloromathane (5×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduce pressure to give the crude 6-amino-2-(2-methoxyethyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (120 mg, 85%) as a yellow oil. LC-MS R_(T)=1.147 min, m/z=239.2 (M+H)⁺.

LCMS (0 to 60% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.147 min, ESI+ found [M+H]=239.2.

Step 3: 1-benzyl-N-[(6S)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1, 3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (23 mg, 0.12 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (40 mg, 0.21 mmol), 6-amino-2-(2-methoxyethyl)-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (25 mg, 0.10 mmol) and 1-hydroxybenzotriazole (28 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduce pressure and the residue was purified by RP-HPLC (acetonitrile 20-45%/0.225% formic acid in water) to afford 1-benzyl-N-[2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (40 mg, 90%) as a white solid. The racemic material was separated by chiral SFC to afford: 1-benzyl-N-[(6S)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.453 min) (11 mg, 27%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 7.38-7.31 (m, 5H), 6.18 (s, 1H), 5.47 (s, 2H), 4.58-4.52 (m, 1H), 4.34-4.30 (m, 1H), 4.25-4.22 (m, 1H), 3.66 (t, J=6.8 Hz, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 2.87-2.83 (m, 3H), 2.27-2.21 (m, 1H). LC-MS R_(T)=1.429 min, m/z=424.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.429 min, ESI+ found [M+H]=424.2.

1-benzyl-N-[(6R)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.281 min) (19.2 mg, 47%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 7.31-7.20 (m, 5H), 6.09 (s, 1H), 5.38 (s, 2H), 4.45-4.41 (m, 1H), 4.26-4.21 (m, 1H), 4.15-4.09 (m, 1H), 3.57 (t, J=6.8 Hz, 2H), 3.26 (s, 3H), 3.23 (s, 3H), 2.78-2.71 (m, 3H), 2.18-2.13 (m, 1H). LC-MS RT=1.361 min, m/z=424.2. LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.361 min, ESI+ found [M+H]=424.2.

SFC condition: (Column: Chiralcel AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% dethyl acetate), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 768

1-[(2-fluorophenyl)methyl]-N-[(6S)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 196. The racemic material was separated by chiral SFC to afford:

-   1-[(2-fluorophenyl)methyl]-N-[(6S)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide     (Peak 1, retention time 4.028 min) (11 mg, 27%) as a white solid. ¹H     NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.42-7.33 (m, 2H), 7.22-7.09     (m, 2H), 6.17 (s, 1H), 5.54 (s, 2H), 4.58-4.51 (m, 1H), 4.36-4.29     (m, 1H), 4.26-4.16 (m, 1H), 3.65 (t, J=6.8 Hz, 2H), 3.35 (s, 3H),     3.31 (s, 3H), 2.86-2.77 (m, 3H), 2.28-2.20 (m, 1H). LC-MS     R_(T)=1.446 min, m/z=442.2 [M+H]⁺. LCMS (10 to 80% acetonitrile in     water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.446     min, ESI+ found [M+H]=442.2.

1-[(2-fluorophenyl)methyl]-N-[(6R)-2-(2-methoxyethyl)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 4.447 min) (25.1 mg, 61%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.44-7.35 (m, 2H), 7.22-7.11 (m, 2H), 6.17 (s, 1H), 5.54 (s, 2H), 4.54-4.50 (m, 1H), 4.36-4.30 (m, 1H), 4.25-4.17 (m, 1H), 3.66 (t, J=6.8 Hz, 2H), 3.35 (s, 3H), 3.32 (s, 3H), 2.85 (t, J=6.6 Hz, 2H), 2.83-2.77 (m, 1H), 2.26-2.20 (m, 1H). LC-MS RT=1.379 min, m/z=442.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over 3.0 mins) retention time 1.379 min, ESI+ found [M+H]=442.2.

SFC conditions: (Column: Chiralcel AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% dethyl acetate), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 769 WX Method 201

1-benzyl-N-[(6S)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl (2-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

A mixture of 2-[6-(tert-butoxycarbonylamino)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]ethyl methanesulfonate (200 mg, 0.50 mmol), potassium carbonate (155 mg, 1.12 mmol), 3-fluoroazetidine (50 mg, 0.67 mmol) and sodium iodide (56 mg, 0.37 mmol) in N,N-dimethylformamide (10 mL) was heated at 50° C. for 6 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, solvent gradient: 0-10% methanol in dichloromethane) to afford tert-butyl N-[2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]carbamate (120 mg, 63%) as a yellow solid, used as is in the next step.

Step 2: 6-amino-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one hydrochloride

To a solution of tert-butyl N-[2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-6-yl]carbamate (120 mg, 0.31 mmol) in ethyl acetate (10 mL) was added hydrochloric acid (4.0 M in ethyl acetate, 1.0 mL, 4.0 mmol). The mixture was stirred at 25° C. for 4 h and concentrated under reduced pressure to afford 6-amino-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one hydrochloride (80 mg, 80%) as a white solid, used in the next step without further purification.

Step 3: 1-benzyl-N-[(6S)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

To a solution of A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (26 mg, 0.13 mmol), 6-amino-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one hydrochloride (40 mg, 0.13 mmol), 1-hydroxybenzotriazole (26 mg, 0.19 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (36 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was stirred at 15° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 3-33/0.05% HCl in water) to afford 1-benzyl-N-[2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (15 mg, 26%) as a white solid. The racemic material was further separated by chiral SFC to give: 1-benzyl-N-[(6 S)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol o[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.263 min) (3.6 mg, 23%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.41-7.30 (m, 5H), 6.18 (s, 1H), 5.48 (s, 2H), 5.24-5.18 (m, 0.5H), 5.09-5.04 (m, 0.5H), 4.57-4.52 (m, 1H), 4.38-4.30 (m, 1H), 4.26-4.17 (m, 1H), 3.76-3.66 (m, 2H), 3.39-3.32 (m, 5H), 2.91-2.81 (m, 3H), 2.71-2.64 (m, 2H), 2.30-2.21 (m, 1H). LCMS R_(T)=1.472 min; m/z=467.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 1.472 min, ESI+ found [M+H]=467.2.

1-benzyl-N-[(6R)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol o[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 5.366 min) (1.8 mg, 11%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.41-7.30 (m, 5H), 6.18 (s, 1H), 5.48 (s, 2H), 5.24-5.18 (m, 0.5H), 5.09-5.04 (m, 0.5H), 4.57-4.52 (m, 1H), 4.38-4.30 (m, 1H), 4.26-4.17 (m, 1H), 3.76-3.66 (m, 2H), 3.39-3.32 (m, 5H), 2.91-2.81 (m, 3H), 2.71-2.64 (m, 2H), 2.30-2.21 (m, 1H). LCMS R_(T)=1.466 min; m/z=467.2 (M+H)⁺. LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 1.466 min, ESI+ found [M+H]=467.2.

SFC condition:Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:iso-propanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature: 40° C.

Example 770

1-[(2-fluorophenyl)methyl]-N-[(6S)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7, 8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 201. The racemic material was separated by chiral SFC to afford:

1-benzyl-N-[(6 S)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol o[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.021 min) (4.7 mg, 29%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.40-7.37 (m, 2H), 7.22-7.13 (m, 2H), 6.20 (s, 1H), 5.56 (s, 2H), 5.33-5.25 (m, 0.5H), 5.22-5.18 (m, 0.5H), 4.58-4.49 (m, 1H), 4.36-4.33 (m, 1H), 4.25-4.22 (m, 1H), 4.15-4.06 (m, 2H), 3.85-3.76 (m, 2H), 3.33 (s, 3H), 3.21-3.18 (m, 2H), 2.86-2.79 (m, 3H), 2.29-2.25 (m, 1H).

LCMS R_(T)=1.486 min; m/z=485.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 1.486 min, ESI+ found [M+H]=485.2.

1-benzyl-N-[(6R)-2-[2-(3-fluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazol o[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 5.051 min) (3.3 mg, 21%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.42-7.36 (m, 2H), 7.23-7.15 (m, 2H), 6.18 (s, 1H), 5.56 (s, 2H), 5.22-5.19 (m, 0.5H), 5.08-5.04 (m, 0.5H), 4.56-4.51 (m, 1H), 4.35-4.31 (m, 1H), 4.25-4.17 (m, 1H), 3.72-3.66 (m, 2H), 3.35-3.29 (m, 5H), 2.89-2.84 (m, 3H), 2.70-2.66 (m, 2H), 2.26-2.21 (m, 1H). LCMS R_(T)=1.482 min; m/z=485.2 (M+H)⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonia water over 3.0 mins) retention time 1.486 min, ESI+ found [M+H]=485.2.

SFC condition:Column: Chiralpak AD-3 100×4.6 mm I.D., 3 umMobile phase: A: CO₂ B:iso-propanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/min Column temperature:40° C.

Example 771 1-[(2-fluorophenyl)methyl]-N-(6S)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-1-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 194. The residue was purified by RP-HPLC (5-35% acetonitrile in water and 0.05% hydrochloric acid) to afford 1-(2-fluorobenzyl)-N-(2-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 33%) as a white solid. The racemic compound was further separated by chiral SFC to afford:

1-[(2-fluorophenyl)methyl]-N-[(6 S)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7, 8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 1.653 min) (5.5 mg, 5%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.40-7.36 (m, 2H), 7.22-7.13 (m, 2H), 6.16 (s, 1H), 5.55 (s, 2H), 4.56-4.51 (m, 1H), 4.36-4.31 (m, 1H), 4.25-4.17 (m, 1H), 4.06-4.04 (m, 1H), 3.65-3.61 (m, 2H), 3.32 (s, 3H), 3.25 (s, 3H), 3.03-3.00 (m, 2H), 2.87-2.80 (m, 3H), 2.68-2.66 (m, 2H), 2.28-2.20 (m, 1H).

LC-MS R_(T)=0.567 min, m/z=497.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.567 min, ESI+ found [M+H]=497.1.

1-[(2-fluorophenyl)methyl]-N-[(6R)-2-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 1.912 min) (4.5 mg, 4%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.43-7.36 (m, 2H), 7.22-7.12 (m, 2H), 6.16 (s, 1H), 5.55 (s, 2H), 4.56-4.51 (m, 1H), 4.34-4.30 (m, 1H), 4.25-4.20 (m, 1H), 4.05-4.02 (m, 1H), 3.64-3.60 (m, 2H), 3.32 (s, 3H), 3.25 (s, 3H), 3.00 (t, J=7.0 Hz, 2H), 2.87-2.78 (m, 3H), 2.68-2.64 (m, 2H), 2.28-2.21 (m, 1H). LC-MS R_(T)=0.574 min, m/z=497.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.574 min, ESI+ found [M+H]=497.2.

SFC condition: column chiralpak AD-3 (50 mm*4.6 mm I.D), 3 um mobile phase: A:CO₂; B: EtOH (0.05% DEA) gradient: hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min. Flow rate: 4 mL/min. Column temperature: 40° C.

Example 772 WX Method 205

1-benzyl-N-[(6S)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: tert-butyl (2-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate

To a solution of 3,3-difluoroazetidine hydrochloride (241 mg, 1.86 mmol) in acetonitrile (5 mL) was added potassium carbonate (513 mg, 3.72 mmol). The mixture was stirred at 25° C. for 3 h and filtered. The filtrate was concentrated under reduced pressure. The residue was added to a mixture of sodium iodide (59 mg, 0.37 mmol), 2-[6-(tert-butoxycarbonylamino)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-2-yl]ethyl methanesulfonate (150 mg, 0.37 mmol) and N,N-diisopropylethylamine (241 mg, 1.86 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was heated at 60° C. for 4 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, solvent gradient: 0-10% methanol in dichloromethane) to give tert-butyl (2-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (100 mg, 67%). LCMS R_(T)=0.547 min, m/z=400.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.547 min, ESI+ found [M+H]=400.0.

Step 2: 6-amino-2-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one hydrochloride

To a solution of tert-butyl (2-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)carbamate (100 mg, 0.25 mmol) in ethyl acetate (5 mL) was added hydrochloric acid (4 M in ethyl acetate, 5.0 mL, 20.0 mmol). The mixture was stirred at 25° C. for 3 h and concentrated under reduced pressure to give the crude 6-amino-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one hydrochloride (84 mg, 99.9%) as a white solid, used in the next step without further purification.

Step 3: 1-benzyl-N-[(6S)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (12 mg, 0.06 mmol), 6-amino-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one hydrochloride (20 mg, 0.06 mmol), 1-hydroxybenzotriazole (12 mg, 0.09 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (11 mg, 0.06 mmol) in N,N-Dimethylformamide (5 mL) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by PR-HPLC (acetonitrile 5-30%/0.05% HCl in water) to give 1-benzyl-N-[(6S)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (10 mg, 7.5%) as a white solid. The racemic material was separated by chiral SFC (AD(250 mm*30 mm, 10 um), 0.1% NH₄OH in EtOH, 50%, 80 mL/min), and further purified by RP-HPLC (acetonitrile 27-57%/0.05% ammonia hydroxide in water) to give:

1-benzyl-N-[(6S)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.921 min) (3.1 mg, 11%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.42-7.35 (m, 5H), 6.21 (s, 1H), 5.50 (s, 2H), 4.59-4.52 (m, 1H), 4.36-4.32 (m, 1H), 4.26-4.22 (m, 1H), 3.67 (t, J=12.0 Hz, 4H), 3.35 (s, 3H), 2.97-2.82 (m, 3H), 2.75-2.65 (m, 2H), 2.29-2.23 (m, 1H). LCMS R_(T)=0.660 min, m/z=485.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.66 min, ESI+ found [M+H]=485.2.

1-benzyl-N-[(6R)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 6.833 min) (3.0 mg, 10%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.42-7.35 (m, 5H), 6.20 (s, 1H), 5.50 (s, 2H), 4.58-4.52 (m, 1H), 4.36-4.32 (m, 1H), 4.26-4.21 (m, 1H), 3.67 (t, J=12.0 Hz, 4H), 3.35 (s, 3H), 2.97-2.82 (m, 3H), 2.75-2.65 (m, 2H), 2.30-2.23 (m, 1H). LCMS R_(T)=0.660 min, m/z=485.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.66 min, ESI+ found [M+H]=485.2.

SFC condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 umMobile phase: A: CO₂ B:ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8 mL/minColumn temperature:40° C.

Example 773

1-[(2-fluorophenyl)methyl]-N-[(6S)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-[(2-fluorophenyl)methyl]-N-[(6R)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Amide coupling prepared in a similar fashion to WX Method 205. The racemic material was separated by chiral SFC to give:

1-[(2-fluorophenyl)methyl]-N-[(6 S)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7, 8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 4.665 min) (2.2 mg, 22%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 7.42-7.35 (m, 2H), 7.20-7.12 (m, 2H), 6.19 (s, 1H), 5.50 (s, 2H), 4.57-4.52 (m, 1H), 4.36-4.32 (m, 1H), 4.24-4.20 (m, 1H), 3.65 (t, J=12.0 Hz, 3H), 3.30 (s, 3H), 2.97-2.82 (m, 3H), 2.75-2.67 (m, 2H), 2.29-2.23 (m, 1H). LCMS R_(T)=0.670 min, m/z=503.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.67 min, ESI+ found [M+H]=503.2.

1-[(2-fluorophenyl)methyl]-N-[(6R)-2-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-methyl-5-oxo-7, 8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 6.242 min) (3.0 mg, 30%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 7.42-7.35 (m, 2H), 7.20-7.12 (m, 2H), 6.19 (s, 1H), 5.57 (s, 2H), 4.57-4.52 (m, 1H), 4.36-4.32 (m, 1H), 4.24-4.20 (m, 1H), 3.64 (t, J=12.0 Hz, 3H), 3.30 (s, 3H), 2.93-2.82 (m, 3H), 2.75-2.67 (m, 2H), 2.29-2.23 (m, 1H). LCMS R_(T)=0.675 min, m/z=503.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5 mins) retention time 0.67 min, ESI+ found [M+H]=503.2.

SFC conditions: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 umMobile phase: A: CO₂ B:ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature:40° C.

Example 774 WX Method 210

1-benzyl-N-[(6S)-4-methyl-5-oxo-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-4-methyl-5-oxo-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

Step 1: ethyl 2-tetrahydropyran-4-ylacetate

A solution of 2-tetrahydropyran-4-ylacetic acid (5.0 g, 34.68 mmol) and cesium carbonate (22.6 g, 69.36 mmol) in N,N-dimethylformamide (60 mL) was added iodoethane (10.8 g, 69.36 mmol) over 10 min at 0° C. The resulting mixture was stirred at 15° C. for 60 h and quenched by addition of water (100 mL). The mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give crude ethyl 2-tetrahydropyran-4-ylacetate (5.8 g, 97%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.21-4.08 (m, 2H), 4.00-3.90 (m, 2H), 3.47-3.35 (m, 2H), 2.24 (d, J=8.0 Hz, 1H), 2.09-1.96 (m, 1H), 1.70-1.58 (m, 2H), 1.42-1.31 (m, 2H), 1.26 (t, J=8.0 Hz, 3H).

Step 2: 3-oxo-4-tetrahydropyran-4-yl-butanenitrile

To a solution of acetonitrile (2 mL, 37.69 mmol) in tetrahydrofuran (60 mL) was added n-butyllithium (2.5 M in Hexanes, 15.1 mL, 37.69 mmol) dropwise at −78° C. After addition, the mixture was stirred at −78° C. for 30 min, then ethyl 2-tetrahydropyran-4-ylacetate (5.8 g, 33.68 mmol) was added dropwise. The mixture was warmed up to room temperature and stirred at 25° C. for another 2 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 3-oxo-4-tetrahydropyran-4-yl-butanenitrile (4.4 g, 76%) as a brown oil, used in the next step without further purification.

Step 3: 5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine

A mixture of 3-oxo-4-tetrahydropyran-4-yl-butanenitrile (4.4 g, 26.31 mmol) and hydrazine hydrate (30 mL) in propan-2-ol (30 mL) was heated at 60° C. for 12 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 7% methanol in dichloromethane) to give 5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine (3.2 g, 67%) as a yellow oil, used as is in the next step. LCMS R_(T)=1.084 min; m/z=182.2 (M+H)⁺. LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3 minutes) retention time 1.084 min, ESI+ found [M+H]=182.2.

Step 4: N-[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl]formamide

A mixture of 5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine (3.2 g, 17.66 mmol) and formic acid (30 mL) was heated at 110° C. for 12 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to give N-[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl]formamide (3.4 g, 92%) as a yellow solid, used as is in the next step. LCMS R_(T)=1.241 min; m/z=210.2 (M+H)⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3.0 mins) retention time 1.241 min, ESI+ found [M+H]=210.2.

Step 5: N-methyl-5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine

To a stirred solution of N-[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl]formamide (3.4 g, 16.25 mmol) in tetrahydrofuran (100 mL) was added borane (1M in tetrahedron, 49.0 mL, 49.0 mmol) dropwise at 0° C. After addition, the mixture was stirred for 2 h at 0° C. and then quenched by addition of methanol (10 mL). The resulting mixture was stirred for another 30 min at 15° C. and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to obtain N-methyl-5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine (1.9 g, 60%) as a light yellow oil, used as is in the next step. LCMS R_(T)=1.316 min; m/z=196.2 (M+H)⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3.0 mins) retention time 1.316 min, ESI+ found [M+H]=196.2.

Step 6: 4-chloro-N-methyl-N-[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl]butanamide

A mixture of 4-chlorobutanoyl chloride (10 mL) and N-methyl-5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-amine (1.5 g, 7.68 mmol) was heated at 60° C. for 1 h and quenched by slow addition of methanol (10 mL). The resulting mixture was stirred for 15 min and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 4-chloro-N-[5-(1-fluorocyclopropyl)-1H-pyrazol-3-yl]-N-methyl-butanamide (1.72 g, 75%) as a yellow oil, used as is in the next step. LCMS R_(T)=0.633 min; m/z=299.8 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.633 min, ESI+ found [M+H]=299.8.

Step 7: 4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

A mixture of cesium carbonate (3.7 g, 11.4 mmol) and 4-chloro-N-methyl-N-[5-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-3-yl]butanamide (1.72 g, 5.73 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25° C. for 15 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (1.1 g, 52%) as a yellow oil, used as is in the next step. LCMS R_(T)=0.583 min; m/z=263.8 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.583 min, ESI+ found [M+H]=263.8.

Step 8: 6-iodo-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-5-one

To a stirred solution of 4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrarazolo[1,5-a][1,3]diazepin-5-one (200 mg, 0.76 mmol) in dichloromethane (60 mL) was slowly added N¹,N¹,N¹,N²-tetramethylethane-1,2-diamine (1.14 mL, 7.59 mmol) and iodotrimethylsilane (1.08 mL, 7.59 mmol) at −15° C. under nitrogen protection. The mixture was stirred at −15° C. for 1.5 h, and then iodine (578 mg, 2.28 mmol) was added. The reaction mixture was stirred for another 2 h, and then quenched by addition of 50% aqueous sodium thiosulfate (10 mL). The resulting mixture was extracted with dichloromethane (2×80 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude 6-iodo-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (150 mg, 53%) as a yellow oil, used in the next step without further purification.

LCMS R_(T)=1.839 min, m/z=390.0 [M+H]⁺. LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.839 min, ESI+ found [M+H]=390.0.

Step 9: 6-azido-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]di azepin-5-one

A mixture of 6-iodo-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (295 mg, 0.76 mmol) and sodium azide (120 mg, 1.85 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The reaction mixture was quenched by addition of 20% aqueous sodium hypochlorite (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-azido-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (230 mg, 99%) as a yellow oil, used in the next step without further purification.

Step 10: 6-amino-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one

A mixture of 6-azido-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (230 mg, 0.76 mmol) and palladium on carbon (10%, 10 mg) in methanol (10 mL) was hydrogenated (15 psi) at 20° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (10% methanol in dichloromethane, R_(f)=0.4) to afford 6-amino-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (140 mg, 66%) as a yellow oil, used as is in the next step.

Step 11: 1-benzyl-N-[(6S)-4-methyl-5-oxo-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide and 1-benzyl-N-[(6R)-4-methyl-5-oxo-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (102 mg, 0.5 mmol), 6-amino-4-methyl-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (140 mg, 0.5 mmol), N,N-dimethyl-3 (methyliminomethylenethyl acetatemino)propan-1-amine hydrochloride (144 mg, 0.75 mmol) and 1-hydroxybenzotrizole (101 mg, 0.75 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was and purified by RP-HPLC (25% to 50% acetonitrile, 0.225% formic acid in water) to afford 1-benzyl-N-[4-methyl-5-oxo-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (130 mg, 55%) as a white solid. The racemic material was further purified by chiral SFC to give:

1-benzyl-N-[(6S)-4-methyl-5-oxo-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 1, retention time 1.543 min) (19.7 mg, 15.2%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.40-7.33 (m, 5H), 6.16 (s, 1H), 5.48 (s, 2H), 4.54-4.48 (m, 1H), 4.37-4.30 (m, 1H), 4.27-4.17 (m, 1H), 3.96-3.90 (m, 2H), 3.44-3.36 (m, 2H), 3.33 (s, 3H), 2.90-2.80 (m, 1H), 2.57-2.53 (m, 2H), 2.30-2.22 (m, 1H), 1.92-1.82 (m, 1H), 1.68-1.62 (m, 2H), 1.35-1.31 (m, 2H). LCMS R_(T)=0.754 min, m/z=464.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.754 min, ESI+ found [M+H]=464.2.

1-benzyl-N-[(6S)-4-methyl-5-oxo-2-(tetrahydropyran-4-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide (Peak 2, retention time 1.875 min) (26.0 mg, 20.0%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.40-7.33 (m, 5H), 6.16 (s, 1H), 5.48 (s, 2H), 4.54-4.48 (m, 1H), 4.38-4.30 (m, 1H), 4.27-4.17 (m, 1H), 3.96-3.90 (m, 2H), 3.44-3.36 (m, 2H), 3.33 (s, 3H), 2.90-2.81 (m, 1H), 2.57-2.53 (m, 2H), 2.30-2.22 (m, 1H), 1.93-1.82 (m, 1H), 1.69-1.62 (m, 2H), 1.35-1.31 (m, 2H). LCMS R_(T)=0.752 min, m/z=464.2 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5 mins) retention time 0.752 min, ESI+ found [M+H]=464.2.

SFC condition: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: A:CO₂ B:methanol (0.05% DEA) Gradient: hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min. Flow rate: 4 mL/min Column temp: 40° C.

Example 775 Suzuki Method 2

1-benzyl-N-(2-(1,2-dimethyl-1H-imidazol-5-yl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

To a microwave vial was charged 1-benzyl-N-(2-bromo-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1,2,4-triazole-3-carboxamide (66 mg, 0.15 mmol), potassium acetate (30 mg, 0.31 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (72 mg, 0.28 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (9.5 mg, 0.0129 mmol)

The solids were dissolved in anhydrous acetonitrile (2 mL) and the vial was sealed and irradiated in a microwave at 140° C. for 15 min. To reaction mixture was added 5-bromo-1,2-dimethyl-imidazole (57 mg, 0.257 mmol), an additional [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (9.5 mg, 0.0129 mmol) and diluted with 1 M potassium carbonate (2 mL). The vial was sealed and irradiated in a microwave at 110° C. for 10 min. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (2×5 mL), brine and dried over sodium sulphate. The filtrate was concentrated to dryness in vacuo and the residue was purified by reverse phase HPLC to afford 1-benzyl-N-(2-(1,2-dimethyl-1H-imidazol-5-yl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide as(8 mg, 12% yield) a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.58 (d, J=7.8 Hz, 1H), 8.34 (s, 2H), 7.45-7.24 (m, 5H), 7.05 (s, 1H), 6.60 (s, 1H), 5.49 (s, 2H), 3.76 (s, 3H), 3.27 (s, 3H), 2.81 (dd, J=63.8, 0.6 Hz, 1H), 2.71-2.56 (m, 1H), 2.32 (s, 3H). LC-MS R_(T)=2.76 min, m/z=460.2 [M+H]⁺. LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.76 min, ESI+ found [M+H]=460.2.

Example 776

1-benzyl-N-(2-(1,2-dimethyl-1H-imidazol-4-yl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Suzuki_Method_2 (7 mg, 10%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 8.32 (s, 2H), 7.46-7.23 (m, 5H), 6.46 (s, 1H), 5.48 (s, 2H), 3.56 (s, 3H), 3.26 (s, 3H), 2.73-2.57 (m, 1H), 2.29 (s, 3H). LC-MS R_(T)=2.27 min, m/z=460.2 [M+H]⁺. LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.72 min, ESI+ found [M+H]=460.2.

Example 777

1-benzyl-N-(4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Suzuki_Method_2. (9 mg, 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.70 (dd, J=2.2, 0.4 Hz, 1H), 7.45-7.20 (m, 5H), 6.58 (s, 1H), 6.50 (d, J=2.2 Hz, 1H), 5.48 (s, 2H), 4.37 (s, 1H), 4.11-3.98 (m, 1H), 3.86 (s, 3H), 3.17 (d, J=5.2 Hz, 4H). LC-MS R_(T)=3.67 min, m/z=446.2 [M+H]⁺. LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins) retention time 3.67 min, ESI+ found [M+H]=446.2.

Example 778

1-benzyl-N-(4-methyl-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Suzuki_Method_1 (13 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.70 (d, J=0.8 Hz, 1H), 7.47-7.19 (m, 4H), 6.50 (s, 1H), 5.48 (s, 2H), 4.45-4.08 (m, 2H), 3.86 (s, 3H), 3.26 (s, 4H), 2.44-2.24 (m, 1H). LC-MS R_(T)=3.63 min, m/z=446.2 [M+H]⁺.

Example 779

(S)-1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1, 3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (Example 443) was further purified by chiral SFC (Chiralpak AD; 150×21.2 mm, 5 um; 30% methanol isocratic elution with Carbon Dioxide) affording (S)-1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5, 6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (13.4 mg, 28.4%) as a white solid:

Analytical data for (S)-1-benzyl-N-(4-methyl-2-(morpholinomethyl)-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide: SFC R_(T) (AD, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.838 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.51 (d, J=7.7 Hz, 1H), 7.42-7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.36-4.24 (m, 2H), 4.14 (m, 1H), 3.57 (m, 4H), 3.48-3.21 (m, 5H), 2.59 (m, 1H), 2.43-2.29 (m, 5H). LCMS R_(T)=2.55 min, m/z=465.2 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.55 min, ESI+ found [M+H]=465.2.

Example 780

1-benzyl-N-(2-(((2-methoxyethyl)amino)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-(((2-methoxyethyl)amino)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was prepared from 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide and 2-methoxyethan-1-amine according to Method GZ7. The crude residue was purified by flash column chromatography (silica gel, 0% to 15% DCM in MeOH) to afford 1-benzyl-N-(2-(((2-methoxyethyl)amino)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (49 mg, 85% Yield) as a tan solid: ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 7.43-7.26 (m, 5H), 6.26 (s, 1H), 5.48 (s, 2H), 4.31 (m, 2H), 4.21-4.07 (m, 1H), 3.66 (d, J=2.1 Hz, 2H), 3.46-3.31 (m, 2H), 3.23 (s, 6H), 2.72 (t, J=5.7 Hz, 2H), 2.58 (m, 1H), 2.41-2.28 (m, 1H). LC-MS R_(T)=2.62 min, m/z=453.2 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.62 min, ESI+ found [M+H]=453.2.

Example 781

(S)-1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was further purified by chiral SFC (Cellulose-1; 150×21.2 mm, 5 um; 25% methanol isocratic elution with Carbon Dioxide) affording (S)-1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (12.7 mg, 34.7%) as a white solid:

Analytical data for (S)-1-benzyl-N-(2-((3-methoxyazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide: SFC R_(T) (Cellulose-1, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.883 min, 100% purity, 100% ee: ¹H 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.51 (d, J=7.7 Hz, 1H), 7.42-7.26 (m, 5H), 6.21 (s, 1H), 5.48 (s, 2H), 4.35-4.23 (m, 2H), 4.13 (m, 1H), 3.94 (p, J=5.8 Hz, 1H), 3.57-3.32 (m, 4H), 3.18 (ds, 6H), 2.86 (m, 2H), 2.58 (m, 1H), 2.41-2.28 (m, 1H). LCMS R_(T)=2.62 min, m/z=465.2 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.62 min, ESI+ found [M+H]=465.2

Example 782

(S)-1-benzyl-N-(2-((3-fluoroazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

1-benzyl-N-(2-((3-fluoroazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazol o[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was prepared from 1-benzyl-N-(2-formyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide was further purified by chiral SFC (Cellulose-1; 150×21.2 mm, 5 um; 35% methanol isocratic elution with Carbon Dioxide) affording (S)-1-benzyl-N-(2-((3-fluoroazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (16.6 mg, 32.8%) as a white solid:

Analytical data for (S)-1-benzyl-N-(2-((3-fluoroazetidin-1-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide: SFC R_(T) (Cellulose-1, 25% methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 min method): 0.879 min, 100% purity, 100% ee. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.52 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 5H), 6.23 (s, 1H), 5.48 (s, 2H), 5.26-5.01 (m, 1H), 4.35-4.23 (m, 2H), 4.14 (m, 1H), 3.63-3.50 (m, 4H), 3.27-3.06 (m, 5H), 2.58 (m, 1H), 2.41-2.28 (m, 1H). LCMS R_(T)=2.59 min, m/z=453.2 (M+H)⁺. LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins) retention time 2.59 min, ESI+ found [M+H]=453.2.

Examples 783-793 are Chiral Separations of Previous Examples as Provided Above Example 794 RIP1 Kinase Inhibition Assays (Biochemical Assay)

The compounds of the present invention were tested for their capacity to inhibit RIP1K activity as described below.

Enzyme Assay:

The ability of the receptor interacting protein kinase (RIPK1) to catalyze the hydrolysis of adenosine-5′-triphosphate (ATP) is monitored using the Transcreener ADP (adenosine-5′-diphosphate) assay (BellBrook Labs). Purified human RIP1 kinase domain (2-375) (50 nM) derived from a baculovirus-infected insect cell expression system is incubated with test compounds for 2 hours in 50 mM Hepes buffer (pH 7.5) containing 30 mM MgCl₂, 1 mM dithiothreitol, 50 uM ATP, 0.002% Brij-35, and 0.5% dimethyl sulfoxide (DMSO). Reactions are quenched by the addition of 1× Bell Brooks Stop buffer B (20 mM Hepes (ph7.5), 40 mM ethylenediaminetetraacetic acid and 0.02% Brij-35) containing an additional 12 mM EDTA and 55 ug/mL ADP2 antibody and 4 nM ADP-AlexaFluor® 633 tracer. The tracer bound to the antibody is displaced by the ADP generated during the RIP1K reaction, which causes a decrease in fluorescence polarization that is measured by laser excitation at 633 nm with a FP microplate reader M1000. Fractional activity was plotted against test article concentration. Using Genedata Screener software (Genedata; Basel, Switzerland), the data were fit to the tight-binding apparent inhibition constant (K_(i) ^(app)) Morrison equation [Williams, J. W. and Morrison, J. F. (1979) The kinetics of reversible tight-binding inhibition. Methods Enzymol 63: 437-67]. The following equation was used to calculate fractional activity and K_(i) ^(app):

${{Fractional}\mspace{14mu} {activity}} = {\frac{v_{i}}{v_{o}} = {1 - \frac{\left( {\lbrack E\rbrack_{T} + \lbrack I\rbrack_{T} + K_{i}^{app}} \right) - \sqrt{\left( {\lbrack E\rbrack_{T} + \lbrack I\rbrack_{T} + K_{i}^{app}} \right)^{2} - {{4\lbrack E\rbrack}_{T}\lbrack I\rbrack}_{T}}}{{2\lbrack E\rbrack}_{T}}}}$

where [E]_(T) and [I]_(T) are the total concentrations of active enzyme and test article, respectively.

Exemplary compounds of the present invention are provided in the following Tables along with their physiochemical characterization and in vitro RIP1 kinase inhibitory activity data. “Method” in the first column of each table refers to the synthetic method(s) used to prepare each compound as shown in the Examples above. In certain examples, chiral column retention times (min) are provided for certain stereoisomers.

Lengthy table referenced here US20170008877A1-20170112-T00001 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20170008877A1-20170112-T00002 Please refer to the end of the specification for access instructions.

The compounds of Tables 3, 4 and 5 below were prepared according to the methods described above. References to specific Methods of the specification are provided as non-limiting examples of how these compounds were prepared.

Lengthy table referenced here US20170008877A1-20170112-T00003 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20170008877A1-20170112-T00004 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20170008877A1-20170112-T00005 Please refer to the end of the specification for access instructions.

The following methods exemplify scaled-up processes for the synthesis of compounds provided herein.

Example A

(S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: N-(3-cyclopropyl-1H-pyrazol-5-yl)formamide

A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (10.0 g, 81.2 mmol) and formic acid (31 mL) was heated at 110° C. for 12 h and subsequently concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to give N-(3-cyclopropyl-1H-pyrazol-5-yl)formamide (8.0 g, 65%) as a yellow solid, used in the next step as is.

Step 2: 3-cyclopropyl-N-methyl-1H-pyrazol-5-amine

To a stirred solution of N-(3-cyclopropyl-1H-pyrazol-5-yl)formamide (8.0 g, 52.9 mmol) in tetrahydrofuran (200 mL) was added lithium aluminumhydride (4.0 g, 105.8 mmol) in small portions at 0° C. After addition, the mixture was stirred for 15 h at 25° C. and subsequently slowly quenched by addition of water (4 mL), aqueous sodium hydroxide (10%, 4 mL) and water (12 mL). To the mixture was added anhydrous sodium sulfate (50 g) and stirred for 30 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude 3-cyclopropyl-N-methyl-1H-pyrazol-5-amine (6.0 g, 83%) as a colorless oil, used in the next step without further purification.

Step 3: 4-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylbutanamide

A mixture of 3-cyclopropyl-N-methyl-1H-pyrazol-5-amine (6.0 g, 43.7 mmol) and 4-chlorobutanoyl chloride (49 mL) was heated at 60° C. for 5 h and cooled to room temperature. The reaction was quenched by slow addition of methanol (100 mL). The resulting mixture was stirred for 30 min and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 4-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylbutanamide (6.5 g, 62%) as a white solid, used as is in the next step.

Step 4: 2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 4-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-N-methylbutanamide (6.0 g, 24.9 mmol) and cesium carbonate (16.2 g, 49.8 mmol) in N,N-dimethylformamide (100 mL) was stirred at 25° C. for 12 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.7 g, 72%) as yellow oil, used as is in the next step. LCMS RT=1.61 min, m/z=206.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.61 min, ESI+ found [M+H]=206.1.

Step 5: 2-cyclopropyl-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a stirred solution of 2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.7 g, 18.0 mmol) in dichloromethane (200 mL) was added N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (16.8 g, 144.2 mmol) and iodotrimethylsilane (28.9 g, 144.2 mmol) at −15° C. The mixture was stirred at −15° C. for 1.5 h and subsequently iodine (13.7 g, 54.0 mmol) was added. The mixture was stirred for another 3 h and quenched by addition of 50% aqueous sodium thiosulfate (50 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 2-cyclopropyl-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (4.5 g, 75%) as colorless oil, used as is in the next step.

Step 6: 6-azido-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 2-cyclopropyl-6-iodo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (4.5 g, 13.6 mmol) and sodium azide (1.3 g, 20.4 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25° C. for 2 h. To the reaction mixture was added ice water (5 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-azido-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.0 g, 90%) as a yellow solid, used as is in the next step. LCMS RT=1.84 min, m/z=247.1 [M+H]+.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.84 min, ESI+ found [M+H]=247.1.

Step 7: (S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

6-azido-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.0 g, 12.2 mmol) and palladium on carbon (10%, 1.3 g, 1.22 mmol) in methyl alcohol (100 mL) was hydrogenated (15 psi) at 25° C. for 12 h and subsequently filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica (solvent gradient: 0-10% methanol in dichloromethane) to afford crude 6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one, which was further separated by chiral SFC (SFC80; Chiralpak OD (250 mm*30 mm, 5 um); Supercritical CO₂/MeOH+NH₃.H₂O=20/20; 50 mL/min) to give:

Peak 1 (Rt=3.113 min):

(S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (600 mg, 22%) as colorless oil. LCMS RT=1.65 min, m/z=221.2 [M+H]⁺.

Peak 2 (Rt=3.525 min)

(R)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (700 mg, 26%) as colorless oil. LCMS RT=1.65 min, m/z=221.2 [M+H]⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.65 min, ESI+ found [M+H]=221.2.

Step 8: (S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (185 mg, 0.91 mmol), (S)-6-amino-2-cyclopropyl-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5 (6H)-one (200 mg, 0.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (261 mg, 1.36 mmol) and 1-hydroxybenzotrizole (184 mg, 1.36 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (30% to 60% acetonitrile, 0.05% HCl) to afford (S)-1-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]di azepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (123 mg, 33%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.40-7.28 (m, 5H), 6.06 (s, 1H), 5.48 (s, 2H), 4.34-4.24 (m, 2H), 4.10-4.03 (m, 1H), 3.19 (s, 3H), 2.61-2.54 (m, 1H), 2.37-2.29 (m, 1H), 1.87-1.81 (m, 1H), 0.88-0.81 (m, 2H), 0.70-0.61 (m, 2H) LCMS RT=0.978 min, m/z=406.2 [M+H]+.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 0.978 min, ESI+ found [M+H]=406.2.

SFC conditions: Column: Chiralcel AD-3 100×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min. Flow rate: 2.8 mL/min. Column temperature: 40° C.

Example B

(S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,5-a[1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: (S)-6-amino-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (5.2 g, 29.0 mmol), 2-hydroxy-5-nitrobenzaldehyde (146 mg, 0.87 mmol) and (2R,3R)-2,3-dihydroxybutanedioic acid (4.36 g, 29.0 mmol) in ethanol (162 mL) was heated to 60° C. for 48 hours and cooled to room temperature. The solid was collected by filtration, washed with ethanol and dried under reduced pressure to afford crude (S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (2R,3R)-2,3-dihydroxybutanedioic acid as a pale yellow solid.

This crude was recrystallized three times from ethanol/H₂O (9:1, 50 mL/g) to afford fine needle crystals (7.0 g, 73%). The crystals (900 mg, 2.7 mmol) were added to a solution of concentrated aqueous ammonia (31 mL) and dichloromethane (75 mL), and stirred at 25° C. for 30 min. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude (6S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (400 mg, 82%) as a colorless oil, used as is in the next step.

Step 2: (S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (23 mg, 0.11 mmol), (S)-6-amino-4-methyl-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-5-one (20 mg, 0.11 mmol), 1-hydroxybenzotriazole (15 mg, 0.11 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (32 mg, 0.17 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 12-42%/0.05% ammonia hydroxide in water) to afford (S)-1-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (23 mg, 50%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.40-7.27 (m, 5H), 6.34 (d, J=1.6 Hz, 1H), 5.48 (s, 2H), 4.40-4.27 (m, 2H), 4.23-4.14 (m, 1H), 3.24 (s, 3H), 2.64-2.55 (m, 1H), 2.43-2.31 (m, 1H). LC-MS R_(T)=0.702 min, m/z=366.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 3.0 mins) retention time 0.702 min, ESI+ found [M+H]=366.0.

SFC conditions: Column: Chiralcel AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 5.0 min and hold 40% for 2.5 min, then 5% of B for 2.5 min. Flow rate: 2.5 mL/min Column temperature: 35° C.

Example C

(S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: N-(3-methyl-1H-pyrazol-5-yl)formamide

A mixture of 5-methyl-1H-pyrazol-3-amine (20.0 g, 206 mmol) and formic acid (100 mL) was heated at 110° C. for 3 h in a sealed vessel and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, O to 10% methanol in dichloromethane) to give N-(3-methyl-1H-pyrazol-5-yl)formamide (22.5 g, 87%) as a yellow solid, used as is in the next step.

Step 2: N,3-dimethyl-1H-pyrazol-5-amine

To a stirred solution of N-(3-methyl-1H-pyrazol-5-yl)formamide (10.0 g, 80 mmol) in tetrahydrofuran (400 mL) was added lithium aluminumhydride (6.0 g, 160 mmol) in small portions at 0° C. After addition, the mixture was stirred for 15 h at 25° C. and subsequently slowly quenched by addition of water (6 mL), aqueous sodium hydroxide (10%, 6 mL) and water (18 mL). To the mixture was added anhydrous sodium sulfate (60 g) and stirred for 30 min. The reaction mixture was filtered and the filtrate was concentrated to afford crude N,3-dimethyl-1H-pyrazol-5-amine (8.0 g, 90%) as colorless oil, used without further purification in the next step.

Step 3: 4-chloro-N-methyl-N-(3-methyl-1H-pyrazol-5-yl)butanamide

A mixture of N,3-dimethyl-1H-pyrazol-5-amine (10.0 g, 90 mmol) and 4-chlorobutanoyl chloride (20 mL) was heated at 60° C. for 5 h. After cooling to room temperature, the reaction mixture was quenched by addition of methanol (5 mL) and stirred for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 5% methanol in dichloromethane) to afford 4-chloro-N-methyl-N-(3-methyl-1H-pyrazol-5-yl)butanamide (6.0 g, 31%) as a yellow oil, used as is in the next step.

Step 4: 2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 4-chloro-N-methyl-N-(3-methyl-1H-pyrazol-5-yl)butanamide (6.0 g, 27.8 mmol) and cesium carbonate (18.1 g, 55.6 mmol) in N,N-dimethylformamide (100 mL) was stirred at 25° C. for 15 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (4.0 g, 80%) as yellow oil, used as is in the next step.

Step 5: 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

To a stirred solution of 2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (2.7 g, 15.1 mmol) in dichloromethane (200 mL) was added N¹,N¹,N¹,N²-tetramethylethane-1,2-diamine (14.0 g, 120.0 mmol) and iodotrimethylsilane (24.0 g, 120.0 mmol) at −15° C. The mixture was stirred at −15° C. for 1.5 h and subsequently iodine (11.5 g, 41.2 mmol) was added. The reaction mixture was stirred for another 3 h and subsequently quenched by addition of 5% aqueous sodium thiosulfate (20 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) to afford 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.0 g, 65%) as a colorless oil, used as is in the next step.

Step 6: 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (3.0 g, 9.8 mmol) and sodium azide (959 mg, 14.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 25° C. for 2 h. To the reaction mixture was added ice water (30 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (2.0 g, 92%) as yellow oil. LCMS RT=1.85 min, m/z=221.2 [M+H]⁺.

LCMS (0 to 30% acetonitrile in water+0.05% ammonium hydroxide over 3 mins) retention time 1.85 min, ESI+ found [M+H]=221.2.

Step 7: (S)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

A mixture of 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (2.0 g, 9.1 mmol) and palladium on carbon (10%, 966 mg) in methyl alcohol (100 mL) was hydrogenated (15 psi) at 25° C. for 12 h and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica (solvent gradient: 0-10% methanol in dichloromethane) to afford the crude 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (1.5 g). The crude was purified by SFC (SFC80; Chiralpak OD (250 mm*30 mm, 5 um); Supercritical CO₂/MeOH+NH₃*H₂O=20/20; 50 mL/min) to give:

Peak 1 (Rt=2.516 min):

(S)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (400 mg, 27%) as a yellow solid, used as is in the next step.

Peak 2 (Rt=2.757 min)

(R)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (350 mg, 23%) as a yellow solid.

Step 8: (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide

A mixture of 1-benzyl-1,2,4-triazole-3-carboxylic acid (251 mg, 1.24 mmol), (S)-6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (200 mg, 1.03 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (296 mg, 1.54 mmol) and 1-hydroxybenzotrizole (209 mg, 1.54 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure and the residue was purified by RP-HPLC (acetonitrile 17-47/0.05% HCl in water) to afford (S)-1-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-1H-1,2,4-triazole-3-carboxamide (221 mg, 56%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 7.39-7.29 (m, 5H), 6.12 (s, 1H), 5.48 (s, 2H), 4.34-4.25 (m, 2H), 4.23-4.06 (m, 1H), 3.21 (s, 3H), 2.59-2.54 (m, 1H), 2.36-2.33 (m, 1H), 2.16 (s, 3H). LCMS RT=0.916 min, m/z=380.4 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3 mins) retention time 0.910 min, ESI+ found [M+H]=380.4.

SFC conditions: Column: Chiralcel AS-H 150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B: ethanol (0.05% DEA), Gradient: hold 5% for 0.5 min, then from 5% to 40% of B in 3.5 min and hold 40% for 2.5 min, then 5% of B for 1.5 min. Flow rate: 3 mL/min Column temperature: 40° C.

Data Based on the Above Scale-Up Experiments:

Example MS (m/z) Ki (μM) Ex Structure Stereo ¹H NMR R.T. Example A 0.016

Single Known Stereo- isomer ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.40-7.28 (m, 5H), 6.06 (s, 1H), 5.48 (s, 2H), 4.34-4.24 (m, 2H), 4.10-4.03 (m, 1H), 3.19 (s, 3H), 2.61- 2.54 (m, 1H), 2.37-2.29 (m, 1H), 1.87-1.81 (m, 1H), 0.88-0.81 (m, 2H), 0.70-0.61 (m, 2H). 406.2 0.978 min Example B 0.013

Single Known Stereo- isomer ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.40- 7.27 (m, 5H), 6.34 (d, J = 1.6 Hz, 1H), 5.48 (s, 2H), 4.40-4.27 (m, 2H), 4.23-4.14 (m, 1H), 3.24 (s, 3H), 2.64-2.55 (m, 1H), 2.43-2.31 (m, 1H). 366.0 0.702 min Example C 0.022

Single Known Stereo- isomer ¹H NMR (400 MHz, DMSO-d₆) δ 8.83(s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.39-7.29 (m, 5H), 6.12 (s, 1H), 5.48 (s, 2H), 4.34-4.25 (m, 2H), 4.23-4.06 (m, 1H), 3.21 (s, 3H), 2.59-2.54 (m, 1H), 2.36-2.33 (m, 1H), 2.16 (s, 3H). 380.4 0.910 min

All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non patent publications referred to in this specification are incorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

LENGTHY TABLES The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20170008877A1). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3). 

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of H and unsubstituted C₁-C₄ alkyl; the A ring is selected from the group consisting of cyclopropyl, 5 to 6 membered aryl, and 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the A ring is optionally substituted with: (a) 1 to 3 substituents selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl, benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl); wherein if a nitrogen atom in the A ring is substituted, the substituent is not halogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, or cyano; (b) 1 substituent selected from the group consisting of C₄-C₆ heterocyclyl, C₅-C₆ heteroaryl, CH₂—(C₄-C₆ heterocyclyl), CH₂CH₂—(C₄-C₆ heterocyclyl), CH₂—(C₅-C₆ heteroaryl), CH₂CH₂—(C₅-C₆ heteroaryl); and optionally a second substituent selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and C₁-C₆ haloalkoxy; or (c) two adjacent substituents which together form phenyl, C₅-C₆ heteroaryl, C₄-C₆ heterocyclyl or C₄-C₆ cycloalkyl; the B ring is tetrazolyl or a 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the B ring is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and cyano; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, or cyano; the C ring is selected from the group consisting of phenyl, 5 to 6 membered heteroaryl, 5 to 7 membered cycloalkyl, and 5 to 7 membered heterocyclyl; wherein the C ring is optionally substituted with: (a) 1 to 4 substituents selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, cyano, phenyl, benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl); wherein if a nitrogen atom in the C ring is substituted, the substituent is not halogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, or cyano; (b) 1 to 2 substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, CH₂—(C₄-C₆ heterocyclyl), CH₂CH₂—(C₄-C₆ heterocyclyl), and unsubstituted C₅-C₆ heteroaryl; or (c) two adjacent substituents which together form phenyl, C₅-C₆ heteroaryl, C₄-C₆ heterocyclyl or C₄-C₆ cycloalkyl; L is selected from the group consisting of a bond, O, S, NH, NCH₃, (CH₂)_(m), CH(CH₃), C(CH₃)₂, CF₂, CH₂O, CH₂S, CH(OH), CH₂NH, and CH₂N(CH₃), or L is absent such that the B ring and the C ring are fused; X is selected from the group consisting of O, S, SO, SO₂, CH₂, C(CH₃)₂, CF₂ and CHCF₃; Z¹ is selected from the group consisting of: (i) C and N when the A ring is a 5 or 6 membered heteroaryl, (ii) C when the A ring is a 5 or 6 membered aryl, and (iii) CH when the A ring is cyclopropyl; m is 1 or 4; and n is 1 or 2; provided that if the A ring is 6 membered aryl or 6 membered heteroaryl, L is absent such that the B ring and the C ring are fused; further provided that if the A ring is a 5 to 6 membered heteroaryl having 3 heteroatoms, two of said heteroatoms must be nitrogen; further provided that if the A ring is unsubstituted 6 membered aryl and L is absent, the fused B and C rings are not unsubstituted indolyl or indolyl substituted by one or two halogen atoms; and further provided that if the B ring is tetrazolyl, L is selected from the group consisting of CH₂ CH(CH₃), C(CH₃)₂, CF₂; and the C ring is phenyl.
 2. A compound according to claim 1 of formula 1(a):

or a pharmaceutically acceptable salt thereof, wherein Z², Z³, and Z⁴ are each independently selected from the group consisting of CR^(Z) and NR⁸; each R^(Z) is independently selected from the group consisting of H, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CH₂(C₃-C₆ cycloalkyl), C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, CH₂(C₄-C₆ cycloalkoxy), CH₂(C₄-C₆ thiocycloalkyl), phenyl, benzyl, 4 to 6 membered heterocyclyl; and 5 to 6 membered heteroaryl; each R⁸ is either absent if the nitrogen atom to which it is attached has three bonds to other atoms, or R⁸ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CH₂(C₃-C₆ cycloalkyl), C₁-C₆ haloalkyl, CH₂(C₄-C₆ cycloalkoxy), CH₂(C₄-C₆ thiocycloalkyl), phenyl, and benzyl; wherein Z¹ is N only if X is CH₂, CF₂, CH(CH₃), CH(CF₃), C(CH₃)₂, or CH(OH); wherein if Z¹ is N, at least one of Z², Z³ or Z⁴ is CR^(Z); wherein, when Z² and Z³ are each independently selected from CR^(Z) and NR⁸, Z² and Z³ together with their respective R^(Z) and R⁸ substituents may form a 6 membered aryl, 6 membered heteroaryl, 5 to 6 membered cycloalkyl or 5 to 6 membered heterocyclyl group; wherein, when Z³ and Z⁴ are each independently selected from CR^(Z) and NR⁸, Z³ and Z⁴ together with their respective R^(Z) and R⁸ substituents may form a 6 membered aryl, 6 membered heteroaryl, 5 to 6 membered cycloalkyl or 5 to 6 membered heterocyclyl group.
 3. A compound of formula I(a) according to claim 2, wherein the compound is of a formula selected from the group consisting of:

wherein each R⁹ is independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms, C₁-C₆ haloalkyl, (C₁-C₄ alkoxy)-C₁-C₂ alkyl, phenyl, benzyl, C₄-C₆ heterocyclyl, CH₂—(C₃-C₆ cycloalkyl), CH₂—(C₃-C₆ cycloalkyl substituted by 1 to 2 fluorine atoms), and CH₂—(C₄-C₆ heterocyclyl).
 4. A compound according to claim 3, wherein each R⁹ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CH₂CH₂OCH₃, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkyl substituted by 1 to 2 fluorine atoms, CH₂—(C₃-C₄ cycloalkyl), CH₂—(C₃-C₄ cycloalkyl substituted by 1 to 2 fluorine atoms), and CH₂—(C₄ heterocyclyl).
 5. A compound according to claim 1 of formula I(b):

or a pharmaceutically acceptable salt thereof, wherein Z¹ is CH; and R² and R³ are each independently selected from the group consisting of H, halo, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, —CH₂(C₃-C₆ cycloalkyl), and —CH₂(C₄-C₆ heterocyclyl); provided that when each of R² and R³ are other than H, one must be C₁-C₄ alkyl.
 6. A compound according to claim 1, wherein:

is selected from the group consisting of:

wherein Y is selected from the group consisting of O, S, SO and SO₂; X¹, X² and X³ are each independently N or CH, wherein 1 or 2 of X¹, X² and X³ is N; X⁴ and X⁵ are each independently N or CH; R^(5a) and R^(5b), are each independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenyl, benzyl, —CH₂(C₃-C₆ cycloalkyl); and 5 to 6 membered heteroaryl; wherein R^(5a) and R^(5b) together with the carbon to which they are attached may form a 3 to 4 membered cycloalkyl or a 4 membered cycloalkoxy; R^(6a) and R^(6b) are each independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH₂(C₃-C₆ cycloalkyl), and 5 to 6 membered heteroaryl; wherein R^(6a) and R^(6b) together with the carbon to which they are attached may form a 3 to 4 membered cycloalkyl or a 4 membered cycloalkoxy; wherein when R^(5a) and R^(6a) are each H, R^(5b) and R^(6b) may together form a 3 or 4 membered cycloalkyl; and wherein only two of R^(5a), R^(5b), R^(6a) and R^(6b) may be other than H in each instance; R⁷ is selected from the group consisting of H and unsubstituted C₁-C₄ alkyl; R¹⁰ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, phenyl, and benzyl; and R¹¹ is selected from the group consisting of H, halogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl.
 7. A compound according to claim 6, wherein

wherein R^(5a) and R^(5b) are each H; or R^(5a) and R^(ha) are each H, and R^(5b) and R^(6b) together form cyclopropyl or cyclobutyl.
 8. A compound according to claim 6, wherein Y is O.
 9. A compound according to claim 6, wherein R^(5a) and R^(5b) are each H.
 10. A compound according to claim 2, wherein

is selected from the group consisting of:


11. A compound according to claim 2, wherein

R¹² is selected from the group consisting of halogen and methyl; and t is 0, 1 or
 2. 12. A compound according to claim 1, wherein the compound is of the formula:

wherein R^(6b) is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH₂(C₃-C₆ cycloalkyl), and 5 to 6 membered heteroaryl.
 13. A compound according to claim 1, wherein the compound is of the formula:

wherein R^(6b) is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH₂(C₃-C₆ cycloalkyl), and 5 to 6 membered heteroaryl.
 14. A compound according to claim 1, wherein the compound is of the formula:

wherein Y is NH or O; and R^(6b) is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH₂(C₃-C₆ cycloalkyl), and 5 to 6 membered heteroaryl.
 15. A compound according to claim 12, wherein R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; and X is CH₂ or O.
 16. A compound according to claim 13, wherein R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; and X is CH₂ or O.
 17. A compound according to claim 14, wherein R¹ is H or methyl; the A ring is 6 membered aryl or 5 membered heteroaryl; Z¹ is C or N; and X is CH₂ or O.
 18. A compound according to claim 1, wherein the compound is selected from the compounds of Table 1, Table 2, Table 3, Table 4 and Table
 5. 19. A compound according to claim 17, wherein the compound is selected from the compounds of Table 1, Table 2, Table 3, Table 4 and Table 5 which have a K_(i) in the RIP1 kinase inhibitory assay of less than or equal to 0.1 μM.
 20. A pharmaceutical composition comprising a compound in accordance with claim 1 and a therapeutically inert carrier.
 21. A method for the treatment or prophylaxis of a disease or disorder in a patient by administering to the patient a compound of claim 1, wherein the disease or disorder is selected from the group consisting of prophylaxis of irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemiareperfusion injury of kidneys, liver and lungs, cisplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD). 